Asymmetric Catalysis, Privileged Ligands and Complexes

Vol. 8, No. 2

Asymmetric Catalysis Privileged Ligands and Complexes

Features include: BINAP/SEGPHOS® Ligands and Complexes Solvias® Ligand Portfolio BINAP, a powerful ligand for for Enantioselective asymmetric catalysis Hydrogenation DuPhos and BPE Phospholane Ligands and Complexes

CFVol8No2FINAL.indd 1 5/15/2008 10:45:06 AM Introduction Vol. 8 No. 2 The quest for novel, efficient chiral transition metal catalysts has been an ongoing endeavor for the past 40 years. Leading this quest is the need from Aldrich Chemical Co., Inc. the pharmaceutical, flavors and fragrances, and agrochemical industries for Sigma-Aldrich Corporation enantiopure molecules. Nearly 85% of new drugs in the market are chiral. 6000 N. Teutonia Ave. This need has led to developments in asymmetric synthesis of chiral ligands Milwaukee, WI 53209, USA and metal complexes. In 2001, the Nobel Prize rewarded the pioneering work of Knowles, Noyori, and Sharpless in the development of catalytic asymmetric synthesis, highlighting the importance of chiral synthesis in chemistry. The pioneering work of Noyori in the 1980s with BINAP ligands began an era To Place Orders where catalysts and ligands became more effective and selective. Telephone 800-325-3010 (USA) Highly effective asymmetric catalytic systems give access to arrays of chiral William Sommer FAX 800-325-5052 (USA) Introduction building blocks used in the synthesis of natural products and drugs. Among Product Manager the plethora of chiral ligands, a few stand out because of their versatility. The Customer & Technical Services common feature of these “privileged” ligands is their C2 symmetry, reducing the number of possible isomeric metal complexes and the number of different Customer Inquiries 800-325-3010 substrates. Among the most recognized family of chiral ligands, BINAP, salens, Technical Service 800-231-8327 bisoxazolines, tartrate ligands, and cinchona alkaloids represent the original SAFC™ 800-244-1173 “privileged ligands” classes that affect a wide variety of transformations under outstanding enantiocontrol and with high yield. A second wave of privileged Custom Synthesis 800-244-1173 ligands has surfaced with the DuPhos phospholanes, DSM phosphoramidites, Flavors & Fragrances 800-227-4563 Solvias Josiphos families, the Reetz and Trost ligands, and ChiralQuest International 414-438-3850 phosphines. These outstanding ligand families have proven their success 24-Hour Emergency 414-438-3850 in industrially useful reactions such as hydrogenations, aldol reactions, and Web Site sigma-aldrich.com asymmetric allylic alkylations, and gained much attention from the synthetic Daniel Weibel Email [email protected] community due to the ready accessibility and modular nature of their design. Product Manager For each of the privileged ligands, representative examples are presented.

® At Sigma-Aldrich , we are committed to providing unprecedented accessibility to chiral, Subscriptions state-of-the-art “privileged ligands” used in a wide variety of C–H, C–C, C–N, and C–O bond-forming transformations. For a complete listing of products related to privileged ligands, please visit To request your FREE subscription to ChemFiles, sigma-aldrich.com/privileged. If you cannot find a product for your research efforts in organic please contact us by: synthesis or drug discovery, we welcome your input. “Please Bother Us.” with your suggestions at Phone: 800-325-3010 (USA) [email protected] or [email protected], or contact your local Sigma-Aldrich office. Mail: Attn: Marketing Communications Table of Contents Aldrich Chemical Co., Inc. Sigma-Aldrich Corporation BINAP/SEGPHOS® Ligands and Complexes ...... 3 P.O. Box 355 ® Solvias Ligand Portfolio for Enantioselective Hydrogenation ...... 14 Milwaukee, WI 53201-9358 DuPhos and BPE Phospholane Ligands and Complexes ...... 34 Email: [email protected] catASium®—Essential Elements for Asymmetric Hydrogenations ...... 40 P-Phos, PhanePhos and BoPhoz™ Ligands ...... 44 ChiralQuest Phosphine Ligands and Complexes ...... 47 International customers, please contact your local Sigma-Aldrich ofﬁ ce. For worldwide contact DSM MonoPhos™ Family ...... 51 information, please see back cover. Reetz Ligands ...... 54 BINOL and Derivatives ...... 56 ChemFiles are also available in PDF format on the Internet at sigma-aldrich.com/chemﬁ les. TADDOL ...... 62 BOX ...... 64 Aldrich brand products are sold through Sigma- PYBOX ...... 67 Aldrich, Inc. Sigma-Aldrich, Inc. warrants that its PHOX ...... 69 products conform to the information contained Salen Ligands ...... 71 in this and other Sigma-Aldrich publications. Cinchona Alkaloids ...... 74 Purchaser must determine the suitability of the QuinoxP* Ligands ...... 79 product for its particular use. See reverse side of invoice or packing slip for additional terms and DIPAMP ...... 81 conditions of sale. DIOP ...... 81 Trost Ligands ...... 82 All prices are subject to change without notice. Landis Ligands ...... 84 ChemFiles (ISSN 1933–9658) is a publication of Aminophosphine Ligands ...... 87 Aldrich Chemical Co., Inc. Aldrich is a member of the Trademarks ...... 88 Sigma-Aldrich Group. © 2008 Sigma-Aldrich Co. Risk & Safety ...... 90

About Our Cover The cover graphic represents the three-dimensional structure of BINAP. The phosphorus atoms are represented in blue. This chiral ligand proved to be one of the most popular, for a variety of asymmetric transformations. 2

CFVol8No2FINAL.indd 2 5/15/2008 10:45:10 AM CF8.2 Extract 4 ed XML 032508 PGD UNP ed0423

BINAP/SEGPHOS® Ligands and Complexes

Since the development of BINAP by Noyori 20 years ago, extensive Ruthenium-Catalyzed Asymmetric Hydrogenation research has been accomplished using this chiral ligand. BINAP proved to be one of the most versatile ligands, catalyzing a wide range of reactions, of Amino Ketones n Complexes and BINAP/SEGPHOS from hydrogenations to Heck cyclizations.1 Ohkuma et al. reported a practical asymmetric hydrogenation reaction using mild hydrogen pressure with a wide scope.5 The access to chiral The research team at Takasago International Corporation developed a alcohols from amino ketones is important for the synthesis of series of ligands and complexes for a plethora of catalyzed asymmetric reactions. Based on a biphenyl architecture, several phosphine ligands physiologically active compounds. In this new process, a diphosphine/ diamine Ru catalyst is utilized. This complex is based on DM-BINAP and have been synthesized. Two large families of ligands can be 1,1‑di-4‑anisyl-2‑isopropyl-1,2‑ethylenediamine (DAIPEN) and a distinguished, BINAP and SEGPHOS (Figure 1). BINAP is based on a ruthenium complex. Using a loading as low as 0.01 mol% of catalyst, the bisnaphthalene backbone with different phosphine derivatives. hydrogenation of various amino ketones was conducted with up to SEGPHOS is based on a bis(1,3‑benzodioxole) backbone with different 99% yield and up to 99.8% ee ( ). To illustrate the relevance of phosphine substituents. BINAP and SEGPHOS are highly reactive and Scheme 4 this new catalyst, Okuma et al. synthesized a series of known molecules selective in a variety of asymmetric hydrogenations. In conjunction with ® used in drug synthesis. ruthenium, rhodium, palladium and copper complexes, these ligands Ligands allow for enantioselectivities of up to >99%. Ruthenium-Catalyzed Asymmetric Rhodium-Catalyzed 1,4‑Addition Reductive Amination of Arylboronic Acids to Coumarins Shimizu and coworkers reported a new protocol en route to chiral amino acid derivatives via reductive amination.6 Using a Ru-DM-SEGPHOS Chen et al. presented the asymmetric synthesis of arylated coumarins.2 complex, a variety of amino esters were obtained in one step from the The importance of this transformation with coumarin precursors is corresponding ketoesters in highly enantioselective fashion (up to illustrated with the synthesis of (R)-tolterodine, a urological drug that can be readily obtained following the asymmetric arylation. Using SEGPHOS >99% ee) (Scheme 5). and Rh(acac)(C H ) , the researchers were able to obtain the desired 2 4 2 References: (1) Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40. (2) Chen, G. arylated coumarins with a yield of 88% and ee of 99.6% (Scheme 1). et al. Org. Lett. 2005, 7, 2285. (3) Tomita, D. et al. J. Am. Chem. Soc. 2005, 127, 4138. (4) Lipshutz, B. H. et al. Org. Lett. 2006, 8, 2969. (5) Ohkuma, T. et al. J. Am. Chem. Soc. Copper-Catalyzed Asymmetric Alkenylation 2000, 122, 6510. (6) Shimizu, H. et al. Acc. Chem. Res. 2007, 40, 1385. and Phenylation Tomita et al. developed a new catalytic enantioselective method for chiral O 3 O alcohol and diarylmethanol synthesis. This new method is a great PR2 PR2 alternative to the kinetic resolution using the Sharpless epoxidation or PR2 O PR2 the asymmetric addition of alkenylzinc reagents to carbonyl compounds, for the synthesis of chiral allylic alcohols. Furthermore, the transformation O can be achieved using air- and moisture-stable alkenylsilanes. Using CuF2 ⋅ H2O with DTBM-SEGPHOS, the aryl aldehyde is reacted with a variety of trimethoxysilane derivatives (Scheme 2). Excellent R = enantioselectivities were obtained from a wide range of aldehydes. BINAP SEGPHOS

CH3 Copper-Catalyzed Asymmetric Hydrosilylations CH3 Lipshutz et al. developed a new method for asymmetric hydrosilylations TolBINAP of various ketones using a preformed DTBM-SEGPHOS ⋅ CuH species in CH3 4 CH3 the presence of excess polymethylhydrosiloxane. High yields and ee's DM-SEGPHOS were reported for a variety of ketones (Scheme 3). These chiral building blocks are precursors for the synthesis of various drugs and naturally C(CH3)3 CH3 occurring molecules. OCH3 XylBINAP

C(CH3)3 DTBM-SEGPHOS

Figure 1

Ph Ph Rh(acac)(C2H4)2 ® H3C B(OH)2 H3C H3C (R)-SEGPHOS N + O O O O OH dioxane/H2O 88%, 99.6% ee (R)-Tolterodine

Scheme 1

O ® OH 1. CuF2•2H2O (R)-DTBM-SEGPHOS •CuH ® OH O Ar Ar + DTBM SEGPHOS R R Si(OMe)3 R H R PMHS 2. TBAF OH OH OH OCH OH OH OH 3 N F3C O O 92%, 99.4% ee CF Cl H3C 3 99%, 94% ee 99%, 97% ee 99%, 99 % ee 88%, 97.1% ee 90%, 95% ee

Scheme 2 Scheme 3

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O COC6H5 OH COC6H5

N OCH3 N OCH3 H2 (S,S)-[Ru] O OCH3 O OCH3

100%, 97% ee OH H N OCH • 3 HCl

O OCH3 Ligands ® F F N N

O NN OH NN (S,S)-[Ru] N N and Complexes H2 F F 97%, 99% ee H C (S,S)-[Ru] = H 3 R2 2 CH P Cl N 3 Ru OCH3 P Cl N R2 H2 BINAP/SEGPHOS

OCH3 CH3

R =

CH3

Scheme 4

− H2 (S)-( )-2,2'-Bis(diphenylphosphino)-1,1'-binaphthalene, 97% AcONH4 − − O Ru-(R)-DM-SEGPHOS NH2 AcOH (S)-( )-BINAP; (S)-( )-(1,1'-Binaphthalene-2,2'-diyl)bis CO2Me CO2Me (diphenylphosphine) 93% ee [76189‑56‑5] P C44H32P2 NH AcOH NH2 AcOH NH2 AcOH NH AcOH 2 FW 622.67 2 CO2Me CO Me CO2Me 2 P CO2Me * S

98% ee 99% ee 99% ee 96% ee

Scheme 5 295825-250MG 250 mg 295825-1G 1g 295825-5G 5g (R)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene, 97% (R)-(+)-(1,1'-Binaphthalene-2,2'-diyl)bis(diphenylphos- (S)-BINAP 8 phine); (R)-(+)-BINAP (S)-(−)-BINAP; (S)-(−)-2,2'-Bis(diphenylphosphino)- [76189‑55‑4] P 1,1'-binaphthalene; (S)-(−)-(1,1'-Binaphthalene-2,2'- C H P 44 32 2 diyl)bis(diphenylphosphine) FW 622.67 P P [76189‑56‑5] C44H32P2 FW 622.67 P

295817-250MG 250 mg 295817-1G 1g (S)-(−)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl 295817-5G 5g 693057-100MG 100 mg 693057-500MG 500 mg (R)-BINAP 8 8 (R)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaph- (R)-H8-BINAP thalene; (R)-(+)-(1,1'-Binaphthalene-2,2'-diyl)bis (R)-(+)-2,2′-Bis(diphenylphospino)-5,5′,6,6′,7,7′,8,8′- (diphenylphosphine); (R)-(+)-BINAP ′ ′ ′ ′ ′ P octahydro-1,1 -binaphthyl; [(1R)-5,5 ,6,6 ,7,7 ,8,8 - [76189‑55‑4] octahydro-[1,1′-binaphthalene]-2,2′-diyl]bis[diphenyl- P C44H32P2 P phosphine] FW 622.67 [139139‑86‑9] P C44H40P2 FW 630.74 (R)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl

693065-100MG 100 mg 692387-50MG 50 mg 693065-500MG 500 mg 692387-100MG 100 mg

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(S)-H8-BINAP 8 (S)-T-BINAP 8 (S)-(−)-2,2′-Bis(diphenylphospino)-5,5′,6,6′,7,7′,8,8′- (S)-(−)-2,2′-p-tolyl-phosphino)-1,1′-binaphthyl CH3 octahydro-1,1′-binaphthyl [100165‑88‑6] [139139‑93‑8] C48H40P2 P C44H40P2 FW 678.78 n Complexes and FW 630.74 P CH3 BINAP/SEGPHOS P

P CH3

693014-50MG 50 mg CH3 693014-100MG 100 mg 693030-100MG 100 mg (R)-(+)-2,2′-Bis(di-p-tolylphosphino)-1,1′-binaphthyl, 97% 693030-500MG 500 mg ® (R)-Tol-BINAP CH 3 8 Ligands [99646‑28‑3] (R)-DM-BINAP C48H40P2 (R)-(+)-2,2′-Bis[di(3,5-xylyl)phosphino]-1,1′-binaph- H3C CH3 FW 678.78 thyl; (R)-(+)-1,1′-Binaphthalene-2,2′-diyl)bis[bis P CH3 CH3 (3,5-dimethyl-phenyl)phosphine] [137219‑86‑4] P P CH3 CH3 C52H48P2 CH3 FW 734.89 P

CH3 CH3 H3C CH3

668966-250MG 250 mg 692379-50MG 50 mg 668966-1G 1g 692379-100MG 100 mg (R)-T-BINAP 8 (S)-DM-BINAP 8 (R)-(+)-2,2′-Bis(di-p-tolylphosphino)-1,1′-binaph- CH3 (S)-(−)-2,2′-Bis[bis(3,5-dimethylphenyl)phosphino]- thyl; (R)-Tol-BINAP H3C CH3 1,1′-binaphthyl; (S)-3,5-Xylyl-BINAP [99646‑28‑3] CH3 [135139‑00‑3] C48H40P2 P P CH3 C52H48P2 FW 678.78 CH3 FW 734.89 CH3 P P CH3

CH3

H3C CH3

CH3 (S)-(-)-2,2′-Bis[di(3,5‑xylyl)phoshino]-1,1′-binaphthyl 693049-100MG 100 mg 693022-50MG 50 mg 693049-500MG 500 mg 693022-100MG 100 mg

(S)-(−)-2,2′-Bis(di-p-tolylphosphino)-1,1′-binaphthyl, 97% (R)-SEGPHOS® 8 (S)-Tol-BINAP (R)-(+)-5,5′-Bis(diphenylphosphino)-4,4′-bi-1,3-benzo- CH3 ‑ ‑ dioxole; [4(R)-(4,4′-bi-1,3-benzodioxole)-5,5′-diyl]bis [100165 88 6] O C48H40P2 [diphenylphosphine] P FW 678.78 [244261‑66‑3] O P CH3 C38H28O4P2 O FW 610.57 P P CH3 O

CH3 692395-50MG 50 mg 692395-100MG 100 mg 668974-250MG 250 mg 668974-1G 1g

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(S)-SEGPHOS® 8 [(R)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl]palladium(II) chloride, 97% (S)-(−)-5,5′-Bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxole [115826‑95‑4] O Ph [210169‑54‑3] C44H32Cl2P2Pd Ph O P P Cl C38H28O4P2 FW 800.00 Pd FW 610.57 P Cl O Ph P Ph O L R: 20/21/22-36/37/38 S: 26-37/39 Ligands 693006-50MG 50 mg 342335-100MG 100 mg ® 693006-100MG 100 mg (R)-[(RuCl(BINAP))2(μ-Cl)3[NH2Me2] 8 (R)-DM-SEGPHOS® 8 and Complexes (R)-(+)-5,5′−Βis[di(3,5-xylyl)phosphino]-4,4′-bi-1,3- Ph Ph H3C CH3 Cl Ph benzodioxole; [(4R)-(4,4′-bi-1,3-benzodioxole)-5,5′- P Ph P H CH3 O Cl Ru Cl Ru Cl H3CNCH3 diyl]bis[bis(3,5-dimethylphenyl)phosphine] P P H P Ph Cl Ph [850253‑53‑1] O Ph Ph CH3 C46H44O4P2 CH3 FW 722.79 O P BINAP/SEGPHOS O Dimethylammonium dichlorotri(μ-chloro)bis[(R)-(+)-2,2′-bis(diphenyl- CH3 phosphino)-1,1′-binaphthyl]diruthenate(II) H3C CH3 [199684‑47‑4] C90H72Cl5NP4Ru2 692476-50MG 50 mg FW 1670.84 692476-100MG 100 mg 692433-100MG 100 mg 692433-500MG 500 mg (S)-DM-SEGPHOS® 8 (S)-(−)-5,5′-Bis(diphenylphosphino)-4,4′-bi-1,3- μ 8 H3C CH3 (S)-[(RuCl(BINAP))2( -Cl)3][NH2Me2] benzodioxole CH3 [210169‑57‑6] O P C46H44O4P2 O Ph Ph CH3 Cl Ph P Ph P H FW 722.79 CH3 O P Cl Ru Cl Ru Cl H3CNCH3 P P H O Ph Cl Ph CH3 Ph Ph

H3C CH3

Dimethylammonium dichlorotri(μ-chloro)bis[(S)-(−)-2,2′-bis(diphenyl- 692999-50MG 50 mg phosphino)-1,1′-binaphthyl]diruthenate(II) 692999-100MG 100 mg [199541‑17‑8] C90H72Cl5NP4Ru2 (R)-DTBM-SEGPHOS® 8 FW 1670.84 (R)-(−)-5,5′-Bis[bis(3,5-di-tert-butyl-4-methoxy- J R: 11 OCH3 phenyl)phosphino]-4,4′-bi-1,3-benzodioxole; t-Bu t-Bu 693138-100MG 100 mg [(4R)-(4,4′-bi-1,3-benzodioxole)-5,5′-diyl]bis[bis t-Bu O (3,5-di-tert-butyl-4-methoxyphenyl)phosphine] 693138-500MG 500 mg P OCH [566940‑03‑2] O 3 t-Bu 8 t-Bu (R)-[(RuCl(H8-BINAP))2(μ-Cl)3][NH2Me2] C74H100O8P2 O FW 1179.53 P OCH3 O t-Bu Ph Ph Ph Ph t-Bu t-Bu P Cl P H H3CNCH3 OCH3 Cl Ru Cl Ru Cl P Cl P H Ph Ph Ph Ph 692484-50MG 50 mg 692484-100MG 100 mg Dimethylammonium dichlorotri(μ-chloro)bis[(R)-(+)-2,2′-bis(diphenylphosphino)-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthyl]diruthenate(II) (S)-DTBM-SEGPHOS® 8 [204933‑84‑6] (S)-(+)-5,5′-Bis[di(3,5-di-tert-butyl-4-methoxy- C90H88Cl5NP4Ru2 OCH3 phenyl)phosphino]-4,4′-bi-1,3-benzodioxole t-Bu t-Bu FW 1686.97 [210169‑40‑7] t-Bu 692190-50MG 50 mg O C74H100O8P2 692190-100MG 100 mg FW 1179.53 O P OCH3 t-Bu t-Bu O P OCH3 O t-Bu t-Bu t-Bu

OCH3

692980-50MG 50 mg 692980-100MG 100 mg

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(S)-[(RuCl(H8-BINAP))2(μ-Cl)3][NH2Me2] 8 (R)-[(RuCl(DM-BINAP))2(μ-Cl)3][NH2Me2] 8

CH Ph Ph CH3 CH3 CH 3 Ph Ph 3 P Cl P H CH3 H3C CH3 Cl Ru Cl Ru Cl H3CNCH3 H3C P Cl P H n Complexes and Ph Ph BINAP/SEGPHOS Ph Ph Cl P Cl P H Ru Cl Ru H3CNCH3 P Cl P Dimethylammonium dichlorotri(μ-chloro)bis[(S)-(−)-2,2′-bis(diphenyl- Cl H phosphino)-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthyl]diruthenate(II) CH3 C H Cl NP Ru H3C CH3 90 88 5 4 2 H3C FW 1686.97 CH3 CH3 CH3 CH3 693324-50MG 50 mg 693324-100MG 100 mg Dimethylammonium dichlorotri(μ-chloro)bis[(R)-(+)-2,2′-bis[di(3,5‑xylyl) ′

phosphino]-1,1 -binaphthyl]diruthenate(II) ® μ 8 C106H104Cl5NP4Ru2 (R)-[(RuCl(T-BINAP))2( -Cl)3[NH2Me2] Ligands FW 1895.27 H C CH R: 11 3 CH3 H3C 3 J 692468-50MG 50 mg 692468-100MG 100 mg Cl P Cl P H Ru Cl Ru H3CNCH3 (S)-[(RuCl(DM-BINAP)) (μ-Cl) ][NH Me ] 8 P Cl Cl P H 2 3 2 2

CH CH3 3 CH3 CH3

CH3 H3C CH3 H3C CH3 H3C CH3 H3C

Cl P Cl P H Dimethylammonium dichlorotri(μ-chloro)bis[(R)-(+)-2,2′-bis(di-p-tolyl- Ru Cl Ru H3CNCH3 phosphino)-1,1′-binaphthyl]diruthenate(II) P Cl Cl P H [749935‑02‑2]

C98H88Cl5NP4Ru2 CH3 H3C CH3 FW 1783.05 H3C CH CH 692441-100MG 100 mg 3 CH3 3 CH3 692441-500MG 500 mg Dimethylammonium dichlorotri(μ-chloro)bis[(S)-(−)-2,2′-bis[di-(3,5‑xylyl) phosphino]-1,1′-binaphthyl]diruthenate(II) (S)-[(RuCl (T-BINAP))2(μ-Cl)3[NH2Me2] 8 C106H104Cl5NP4Ru2 FW 1895.27

H3C CH3 R: 36/37 S: 26-36 CH3 H3C L 693154-50MG 50 mg

Cl 693154-100MG 100 mg P Cl P H Ru Cl Ru H CNCH 3 3 ® 8 P Cl Cl P H (R)-[(RuCl(SEGPHOS ))2(μ-Cl)3][NH2Me2]

O Ph Ph O Ph Ph H O P Cl P O H3C CH3 H3C CH3 Cl Ru Cl Ru Cl H3CNCH3 O P Cl P O H Ph Ph Ph Dimethylammonium dichlorotri(μ-chloro)bis[(S)-(−)-2,2′-bis(di-p-tolyl- O Ph O phosphino)-1,1′-binaphthyl]diruthenate(II) [309735‑86‑2] Dimethylammonium dichlorotri(μ-chloro)bis[(R)-(+)-5,5′-bis(diphenyl- C98H88Cl5NP4Ru2 phosphino)-4,4′-bi-1,3‑benzodioxole]diruthenate(II) FW 1783.05 [346457‑41‑8] R: 11 J C78H64Cl5NO8P4Ru2 FW 1646.64 693146-100MG 100 mg 692204-50MG 50 mg 693146-500MG 500 mg 692204-100MG 100 mg

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® (S)-[(RuCl(SEGPHOS ))2(μ-Cl)3][NH2Me2] 8 (R)-RuCl[(p-cymene)(BINAP)]Cl 8 Chloro[(R)-(+)-2,2′-bis(diphenylphosphino)- O Ph Ph CH3 Ph Ph O ′ Ph Ph 1,1 -binaphthyl](p-cymene)ruthenium(II) Cl H P O P Cl P O chloride Cl Ru Cl Ru Cl H3CNCH3 Ru O O ‑ ‑ Cl P Cl P H [145926 28 9] P CH Ph Ph 3 Ph C H Cl P Ru Ph Ph H3C O Ph O 54 46 2 2 FW 928.87 Dimethylammonium dichlorotri(μ-chloro)bis[(S)-(−)-5,5′-bis(diphenyl- 692492-100MG 100 mg phosphino)-4,4′-bi-1,3‑benzodioxole]diruthenate(II) 692492-500MG 500 mg Ligands [488809‑34‑3] ® C78H64Cl5NO8P4Ru2 (S)-RuCl[(p-cymene(BINAP)Cl 8 FW 1646.64 Chloro[(S)-(−)-2,2′-bis(diphenylphosphino)- Ph Ph CH3 693162-50MG 50 mg 1,1′−binaphthyl](p-cymene)ruthenium(II) P Cl

and Complexes 693162-100MG 100 mg chloride Ru [130004‑33‑0] P Cl CH3 ® H C (R)−[(RuCl(DM−SEGPHOS )2(μ−Cl)3][NH2Me2] 8 C54H46Cl2P2Ru Ph Ph 3 FW 928.87

CH3 CH CH3 R: 36/37/38 S: 26 3 CH3 L CH3 H3C CH3 692972-100MG 100 mg BINAP/SEGPHOS H3C O O 692972-500MG 500 mg Cl P Cl P O O H Ru Cl Ru H3CNCH3 8 O P Cl P O (R)-RuCl[p-cymene)(H8-BINAP)]Cl Cl H O O Chloro[(R)−(+)−2,2′−bis(diphenylphosphino) CH3 H3C − ′ ′ ′ ′− − ′− Ph H3C CH3 5,5 ,6,6 ,7,7 ,8,8 octahydro 1,1 binaphthyl] Ph Cl CH3 P (p-cymene)ruthenium(II) chloride Ru CH CH 3 CH3 3 CH3 P Cl C54H54Cl2P2Ru Ph CH Ph 3 FW 936.93 H3C Dimethylammonium dichlorotri(μ−chloro)bis[(R)−(+)−5,5′−bis[di(3,5 − − ′− − − xylyl)phosphino] 4,4 bi 1,3 benzodioxole]diruthenate(II) 692514-50MG 50 mg C94H96Cl5NO8P4Ru2 FW 1871.07 692514-100MG 100 mg 692212-50MG 50 mg (S)-RuCl[(p-cymene)(H8-BINAP)]Cl 8 692212-100MG 100 mg Chloro[(S)-(−)-2,2′−bis(diphenylphosphino)- Ph Ph CH3 ® 5,5′,6,6′,7,7′,8,8′-octahydro-1,1′−binaphthyl] (S)-[(RuCl(DM-SEGPHOS ))2(μ-Cl)3][NH2Me2] 8 P Cl (p-cymene)ruthenium(II) chloride Ru Cl CH CH3 C54H54Cl2P2Ru P 3 CH3 CH3 CH3 FW 936.93 Ph Ph H3C CH3 H3C CH3 H3C O O 693111-50MG 50 mg Cl P Cl P O O H Ru Cl Ru 693111-100MG 100 mg H3CNCH3 O P Cl P O Cl H O O (R)-RuCl[(p-cymene)(T-BINAP)]Cl 8

H3C H3C CH3 Chloro[(R)-(+)-2,2′-bis(di-p-tolylphosphino)- CH3 H3C CH3 1,1′-binaphthyl](p-cymene)ruthenium(II) CH3 CH3 CH3 CH3 chloride [131614‑43‑2] CH3 Dimethylammonium dichlorotri(μ-chloro)bis[(S)-(−)-5,5′-bis[di(3,5‑xylyl) C H Cl P Ru P Cl ′ ‑ 58 54 2 2 phosphino]-4,4 -bi-1,3 benzodioxole]diruthenate(II) FW 984.97 Ru C94H96Cl5NO8P4Ru2 P Cl CH3 FW 1871.07 H3C J R: 11

693170-50MG 50 mg H3C CH3 693170-100MG 100 mg 692506-100MG 100 mg 692506-500MG 500 mg

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(S)-RuCl[(p-cymene)(T-BINAP)]Cl 8 (S)-RuCl[(p-cymene)(SEGPHOS®)]Cl 8 Chloro[(S)-(−)-2,2′-bis(di-p-tolylphosphino)- Chloro[(S)-(−)-5,5′-bis(diphenylphosphino)- H3C CH3 O Ph Ph CH3 1,1′-binaphthyl](p-cymene)ruthenium(II) 4,4′-bi-1,3-benzodioxole](p-cymene) Cl O P chloride ruthenium(II) chloride Ru O [228120‑95‑4] CH3 C48H42Cl2O4P2Ru P Cl n Complexes and CH BINAP/SEGPHOS Cl 3 C58H54Cl2P2Ru P FW 916.77 O Ph Ph H3C FW 984.97 Ru P Cl CH3 692956-50MG 50 mg H3C 692956-100MG 100 mg

® H3C CH3 (R)-RuCl[(p-cymene)(DM-SEGPHOS )]Cl 8 − − ′− − Chloro[(R) (+) 5,5 bis[di(3,5 xylyl) CH 692964-100MG 100 mg CH3 3 phosphino]−4,4′−bi−1,3−benzodioxole](p 692964-500MG 500 mg H C CH −cymene)ruthenium(II) chloride 3 3 ® CH C56H58Cl2O4P2Ru O 3 Ligands (R)−RuCl[(p−cymene)(DM−BINAP)]Cl 8 FW 1028.98 Cl O P Ru Chloro[(R)−(+)−2,2′−bis(di−(3,5−xylyl) O CH CH3 P Cl phosphino)−1,1′−binaphthyl](p−cymene) 3 CH3 O H3C ruthenium(II) chloride H3C CH3 H3C CH3 C62H62Cl2P2Ru CH3 FW 1041.08 Cl P CH3 CH3 Ru P Cl CH3 692417-50MG 50 mg H3C 692417-100MG 100 mg H3C CH3

CH ® 3 CH3 (S)-RuCl[(p-cymene)(DM-SEGPHOS )]Cl 8 – ′ Chloro[(S)-( )-5,5 -bis[di(3,5-xylyl)phosphino]- CH 692409-50MG 50 mg CH3 3 4,4′-bi-1,3-benzodioxole](p-cymene) 692409-100MG 100 mg ruthenium(II) chloride H3C CH3 C56H58Cl2O4P2Ru O CH3 (S)-RuCl[(p-cymene)(DM-BINAP)]Cl 8 FW 1028.98 Cl O P Ru Chloro[(S)-(−)-2,2′-bis(di-(3,5-xylyl) O CH CH3 P Cl phosphino)-1,1′-binaphthyl](p-cymene) 3 CH3 O H3C ruthenium(II) chloride H3C CH3 H3C CH3 C62H62Cl2P2Ru CH3 FW 1041.08 Cl P CH3 CH3 Ru P Cl CH3 692948-50MG 50 mg H3C 692948-100MG 100 mg H3C CH3

CH ® 3 CH3 (R)-RuCl[(p-cymene)(DTBM-SEGPHOS )]Cl 8 Chloro[(R)−(−)5,5′−bis[bis(3,5−di−tert−butyl H CO t-Bu OCH3 693103-50MG 50 mg −4−methoxyphenyl)phosphino]−4,4′−bi−1,3 3 t-Bu 693103-100MG 100 mg −benzodioxole](p−cymene)ruthenium(II) t-Bu t-Bu

chloride O CH3 ® (R)−RuCl[(p−cymene)(SEGPHOS )]Cl 8 C84H114Cl2O8P2Ru Cl O P FW 1485.72 Ru Chloro[(R)-(+)-5,5′-bis(diphenylphosphino)- O O Ph Ph CH3 P Cl 4,4′−bi−1,3−benzodioxole](p-cymene) CH3 Cl O H3C O P ruthenium(II) chloride Ru t-Bu O t-Bu C48H42Cl2O4P2Ru P Cl CH3 t-Bu H C H CO OCH FW 916.77 O Ph Ph 3 3 t-Bu 3

692522-50MG 50 mg 692425-50MG 50 mg 692522-100MG 100 mg 692425-100MG 100 mg

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® (S)-RuCl[(p-cymene)(DTBM-SEGPHOS )]Cl 8 RuCl2[(R)−DM−BINAP][(R,R)−DPEN] 8 Chloro[(S)-(+)-5,5′-bis[di(3,5-di-tert-butyl-4- Dichloro[(R)−2,2′−bis[di(3,5−xylyl)phosphino] t-Bu OCH3 CH3 CH3 methoxyphenyl)phosphino]-4,4′-bi-1,3-benzo- H3CO t-Bu −1,1′−binaphthyl][(1R,2R)−1,2−diphenyl- t-Bu H C CH dioxole](p-cymene)ruthenium(II) chloride t-Bu ethylenediamine]ruthenium(II) 3 3 ‑ ‑ C84H114Cl2O8P2Ru O CH3 [220114 38 5] H H FW 1485.72 P Cl N P Cl C66H64Cl2N2P2Ru O Ru Ru FW 1119.15 N O P Cl P Cl H H CH3 O H3C t-Bu H3C CH3

Ligands t-Bu

t-Bu OCH3 CH ® CH3 3 H3CO t-Bu

692301-50MG 50 mg 693073-50MG 50 mg 692301-100MG 100 mg and Complexes 693073-100MG 100 mg

8 8 RuCl2[(S)-(DM-BINAP)][(S,S)-DPEN] RuCl2[(R)−DM−BINAP][(R)−DAIPEN] Dichloro[(S)-(−)-2,2′-bis[di(3,5-xylyl) CH3 CH3 CH3 CH3 phosphino]-1,1′-binaphthyl][(1S,2S)-(−)-1,2- H3C CH3 H3C CH3 diphenylethylenediamine]ruthenium(II) BINAP/SEGPHOS CH [220114‑03‑4] H H H H 3 P Cl N P Cl CH3 C66H64Cl2N2P2Ru N Ru Ru FW 1119.15 N N OCH3 P Cl P Cl H H H H

H3C CH3 H3C CH3 OCH3 CH3 CH3 CH3 CH3

Dichloro[(R)−2,2′−bis[di(3,5−xylyl)phosphino]−1,1′−binaphthyl][(2R)−1,1 693251-50MG 50 mg −bis(4−methoxyphenyl)−3−methyl−1,2−butanediamine]ruthenium(II) 693251-100MG 100 mg [220114‑32‑9] C H Cl N O P Ru ® 71 74 2 2 2 2 RuCl2[(R)-DM-SEGPHOS ][(R)-DAIPEN] 8 FW 1221.28

692255-50MG 50 mg CH3 CH3 692255-100MG 100 mg H3C CH3 O CH H H 3 8 Cl CH3 RuCl2[(S)-(DM-BINAP)][(S)-DAIPEN] O P N Ru OCH O Cl N 3 CH3 CH3 P H H O H3C CH3 H3C CH CH3 H H 3 OCH3 Cl CH3 P N CH3 CH3 Ru N OCH3 P Cl H H Dichloro[(R)-5,5′-bis[di(3,5‑xylyl)phosphino]-4,4′-bi-1,3‑benzodioxole] [(2R)-1,1‑bis(4‑methoxyphenyl)-3‑methyl-1,2‑butanediamine]ruthenium H3C CH3 (II) OCH3 C65H70Cl2N2O2P2Ru CH CH3 3 FW 1145.19 Dichloro[(S)-(−)-2,2′-bis[di(3,5‑xylyl)phosphino]-1,1′-binaphthyl][(2S)-(+)- 692328-50MG 50 mg 1,1‑bis(4‑methoxyphenyl)-3‑methyl-1,2‑butanediamine]ruthenium(II) 692328-100MG 100 mg [220114‑01‑2] C71H74Cl2N2O2P2Ru FW 1221.28 693227-50MG 50 mg 693227-100MG 100 mg

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® RuCl2[(S)-(DM-SEGPHOS )][(S)-DAIPEN] 8 (S)-Ru(OAc)2(BINAP) 8 Diacetato[(S)-(−)-2,2′-bis(diphenylphosphino)- CH3 CH3 Ph Ph CH3 1,1′-binaphthyl]ruthenium(II) O P H3C CH3 [261948‑85‑0] O Ru O O CH H H 3 C48H38O4P2Ru P

O Complexes and P Cl CH3 CH BINAP/SEGPHOS O N FW 841.83 Ph 3 Ru Ph N OCH3 O P Cl H H O 693189-100MG 100 mg

H3C 693189-500MG 500 mg CH3 OCH3

CH3 CH3 (R)-Ru(OAc)2(H8-BINAP) 8 Dichloro[(S)-(−)-5,5′-bis[di(3,5‑xylyl)phosphino]-4.4′-bi-1,3‑benzodioxole] Diacetato[(R)-2,2′-bis(diphenylphosphino)- ‑ ‑ ‑ ‑ Ph Ph CH3 [(2S)-(+)-1,1 bis(4 methoxyphenyl)-3 methyl-1,2 butanediamine] 5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthyl] O P ruthenium(II) ruthenium(II) O ® Ru O

C65H70Cl2N2O6P2Ru ‑ ‑ Ligands [374067 51 3] P O FW 1209.18 CH C48H46O4P2Ru Ph 3 Ph 693219-50MG 50 mg FW 849.89 693219-100MG 100 mg 692166-50MG 50 mg 692166-100MG 100 mg ® 8 RuCl2[(R)−(DM−SEGPHOS )][(R,(R))−(DPEN)] Dichloro[(R)−5,5′−bis[di(3,5−xylyl)phosphino] 8 CH3 CH3 (S)-Ru(OAc)2(H8-BINAP) −4,4′−bi−1,3−benzodioxole][(1R,2R)−1,2 H C Diacetato[(S)-(−)-2,2′-bis(diphenylphosphino)- −diphenylethylenediamine]ruthenium(II) 3 CH3 Ph Ph CH3 5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthyl] O O P C60H60Cl2N2O2P2Ru H H O Cl ruthenium(II) FW 1075.05 O P N Ru O Ru ‑ ‑ [142962 95 6] P O O Cl N CH P C48H46O4P2Ru Ph 3 H H Ph O FW 849.89

CH3 R: 36/37 S: 26 H3C L CH CH3 3 693278-50MG 50 mg 693278-100MG 100 mg 692336-50MG 50 mg 692336-100MG 100 mg (R)-Ru(OAc)2(T-BINAP) 8

® Diacetato[(R)-2,2′-bis(di-p-tolylphosphino)-1,1′-bi- RuCl [(S)-(DM-SEGPHOS )][(S,S)-DPEN] 8 H3C CH3 2 naphthyl]ruthenium(II) Dichloro[(S)-5,5′-bis[di(3,5-xylyl)phosphino]- ‑ ‑ CH3 CH3 [116128 29 1] CH3 4,4′-bi-1,3-benzodioxole][(1S,2S)-1,2- C52H46O4P2Ru O H3C CH3 P diphenylethylenediamine]ruthenium(II) FW 897.94 O O Ru C60H60Cl2N2O4P2Ru H H O Cl P FW 1107.05 O P N O Ru CH3 N O P Cl H H O H3C CH3 H3C CH3

CH CH3 3 692239-100MG 100 mg 692239-500MG 500 mg 693200-50MG 50 mg 693200-100MG 100 mg 8 (S)-Ru(OAc)2(T-BINAP) − ′ 8 Diacetato[(S)-( )-2,2 -bis(di-p-tolylphosphino)- H C (R)-Ru(OAc) (BINAP) 3 CH3 2 1,1′-binaphthyl]ruthenium(II) ′ ′ Diacetato[(R)-(+)-2,2 -bis(diphenylphosphino)-1,1 CH [106681‑15‑6] Ph Ph 3 −binaphthyl]ruthenium(II) O C H O P Ru CH3 P 52 46 4 2 O O [325146‑81‑4] FW 897.94 P Ru O O Ru C48H38O4P2Ru P O O FW 841.83 Ph Ph CH3 P O CH3

692220-100MG 100 mg

692220-500MG 500 mg H3C CH3 L R: 36/37 S: 26-36 693197-100MG 100 mg 693197-500MG 500 mg

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® (R)-Ru(OAc)2(DM-BINAP) 8 (S)-Ru(OAc)2(DM-SEGPHOS ) 8 Diacetato[(R)-2,2′-bis[di(3,5-xylyl)phosphino]- Diacetato[(S)-(−)-5,5′-bis[di(3,5-xylyl)phosphino]- CH3 CH3 CH3 CH3 1,1′-binaphtyl]ruthenium(II) 4,4′-bi-1,3-benzodioxole]ruthenium(II) H C H C [374067‑50‑2] 3 CH3 C50H50O8P2Ru 3 CH3 C56H54O4P2Ru CH3 FW 941.94 O CH3 O O FW 954.04 P P O O O Ru O Ru O O P O P O CH CH 3 O 3

H C CH3 H C CH3

Ligands 3 3

® CH3 CH3 CH3 CH3

692158-50MG 50 mg 693235-50MG 50 mg

and Complexes 692158-100MG 100 mg 693235-100MG 100 mg

® (S)-Ru(OAc)2(DM-BINAP) 8 Takasago (R)-SEGPHOS /BINAP Ligands kit − ′ Diacetato[(S)-( )-2,2 -bis[di(3,5-xylyl)phosphino]- CH Components ′− 3 CH3 1,1 binaphthyl]ruthenium(II) (R)-DM-BINAP (Aldrich 692379) 50mg H C [374067‑49‑9] 3 CH3 (R)-H -BINAP (Aldrich 692387) 50mg

BINAP/SEGPHOS 8 ® C56H54O4P2Ru CH3 (R)-SEGPHOS (Aldrich 692395) 50mg O ® FW 954.04 P (R)-DM-SEGPHOS (Aldrich 692476) 50mg O ® Ru O (R)-DTBM-SEGPHOS (Aldrich 692484) 50mg P O (R)-T-BINAP (Aldrich 693049) 100mg CH3 (R)-BINAP (Aldrich 693065) 100mg 695270-1KT 1 kit H3C CH3

CH3 CH 3 Takasago (R)-Ru Acetate Kit I

693286-50MG 50 mg Components

693286-100MG 100 mg (R)-Ru(OAc)2(DM-BINAP) (Aldrich 692158) 50mg (R)-Ru(OAc)2(H8-BINAP) (Aldrich 692166) 50mg ® ® (R)-Ru(OAc)2(SEGPHOS ) (Aldrich 692174) 50mg (R)-Ru(OAc)2(SEGPHOS ) 8 ® (R)-Ru(OAc)2(DM-SEGPHOS ) (Aldrich 692182) 50mg ′ ′ (R)-Ru(OAc)2(BINAP) (Aldrich 692220) 100mg Diacetato[(R)-5,5 -bis(diphenylphosphino)-4,4 -bi- CH O Ph Ph 3 (R)-Ru(OAc) (T-BINAP) (Aldrich 692239) 100mg 1,3-benzodioxole]ruthenium(II) O 2 O P O C42H34O8P2Ru 695300-1KT 1 kit Ru O FW 829.73 O P O Ph CH O Ph 3 Takasago (R)-Ru dimethylamine Kit I Components 692174-50MG 50 mg (R)-[(RuCl(H8-BINAP))2(μ-Cl)3][NH2Me2] (Aldrich 692190) 50mg 692174-100MG 100 mg ® (R)-[(RuCl(SEGPHOS ))2(μ-Cl)3][NH2Me2] (Aldrich 692204) 50mg ® (R)−[(RuCl(DM−SEGPHOS )2(μ−Cl)3][NH2Me2] (Aldrich 692212) 50mg ® 8 μ (S)-Ru(OAc)2(SEGPHOS ) (R)-[(RuCl(BINAP))2( -Cl)3[NH2Me2] (Aldrich 692433) 100mg (R)-[(RuCl(T-BINAP)) (μ-Cl) [NH Me ] (Aldrich 692441) 100mg − ′ ′ 2 3 2 2 Diacetato[(S)-( )-5,5 -bis(diphenylphosphino)-4,4 - CH μ O Ph Ph 3 (R)-[(RuCl(DM-BINAP))2( -Cl)3][NH2Me2] (Aldrich 692468) 50mg bi-1,3-benzodioxole]ruthenium(II) O P 695297-1KT 1 kit [373650‑12‑5] O O Ru O O C42H34O8P2Ru P O CH Takasago (R,R)-Ru diamine Kit I FW 829.73 O Ph Ph 3 Components 693243-50MG 50 mg RuCl2[(R)−DM−BINAP][(R)−DAIPEN] (Aldrich 692255) 50mg 693243-100MG 100 mg RuCl2[(R)−DM−BINAP][(R,R)−DPEN] (Aldrich 692301) 50mg ® RuCl2[(R)-DM-SEGPHOS ][(R)-DAIPEN] (Aldrich 692328) 50mg − − ® − ® RuCl2[(R) (DM SEGPHOS )][(R,(R)) (DPEN)] (Aldrich 692336) 50mg (R)-Ru(OAc)2(DM-SEGPHOS ) 8 695319-1KT 1 kit Diacetato[(R)-5,5′-bis[di(3,5-xylyl)phosphino]- CH3 CH3 4,4′-bi-1,3-benzodioxole]ruthenium(II) H C Takasago (R)-Ru Cymene Kit I C50H50O8P2Ru 3 CH3 FW 941.94 O CH3 Components O P O O (R)−RuCl[(p−cymene)(DM−BINAP)]Cl (Aldrich 692409) 50mg Ru O ® O (R)-RuCl[(p-cymene)(DM-SEGPHOS )]Cl (Aldrich 692417) 50mg P O (R)-RuCl[(p-cymene)(DTBM-SEGPHOS®)]Cl (Aldrich 692425) 50mg CH O 3 (R)-RuCl[(p-cymene)(BINAP)]Cl (Aldrich 692492) 100mg (R)-RuCl[(p-cymene)(T-BINAP)]Cl (Aldrich 692506) 100mg H3C CH3 (R)-RuCl[p-cymene)(H8-BINAP)]Cl (Aldrich 692514) 50mg ® CH3 CH3 (R)−RuCl[(p−cymene)(SEGPHOS )]Cl (Aldrich 692522) 50mg 695289-1KT 1 kit 692182-50MG 50 mg 692182-100MG 100 mg

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Solvias® Ligand Portfolio for Enantioselective Hydrogenation

O OH Hans-Ulrich Blaser, Garrett Hoge, Matthias Lotz, Benoît Pugin, Ru / A101 X X [4-6] Anita Schnyder and Felix Spindler R R Solvias AG, P.O. Box, CH-4002 Basel, Switzerland R = alkyl, (subst) Ph, Np 1-10 bar, 40-80 °C 88-97% ee Contact: Dr. Garrett Hoge, Product Manager Catalysis, X = COOR', SO2Ph [email protected] OH O [Ru(p-cymene)I2]2 / A101-1 H H N Today's Solvias Ligand Portfolio has its roots in the development of the N s/c 4000, 20 h R [7] R O Josiphos ligands and the successful implementation in the O Cl — Cl MeOH, 1 N HCl (S)-metolachlor process the largest industrial enantioselective 80 bar, 60°C 90 - 93% ee manufacturing process—in the former Ciba-Geigy. Over the last decade, bench scale, Solvias several additional ligand families have been added, either via Solvias' O OH 1 COOMe own research or via licensing from other companies. The central COOMe Ru / A101 [8] concept for all Solvias ligands is their modularity, usually via the Cl Cl introduction of different phosphino moieties in the very last stages of MeO CH2Cl2 MeO Ligand Portfolio their synthesis. This allows the easy tuning of the steric and electronic 95% ee, 92% de

® properties and, thereby, the adaptation to the needs of a specific reaction. All ligands in the Solvias portfolio are available on a research O 1) Ir / A101 OH AcOH / NaOAc COOMe COOMe [9] scale with very short lead times; several ligands are being produced Ar Ar NHBz regularly in multikilogram quantities. The number of ligands within the NH2.HCl 2) Bz2O, TEA, THF different families varies between 10 to >100; therefore, it is not practical 92% ee, dr >99 Solvias to have all of them available in a catalog. For this reason the members offered via Sigma-Aldrich® are a selection representing different steric Figure 1 and electronic properties. Further derivatives for optimization or fine tuning are usually available on request from Solvias.

OH OH MeOBIPHEP Ru / A101 Ru / p-Tol-MeOBIPHEP 20 °C, 60 bar In many respects, the catalytic profile of the MeOBIPHEP ligands is rather 20 °C, 60 bar ee 99%; TON 30,000; TOF 1500 h-1 de 99%; TON 150,000; TOF 13,000 h-1 similar to that of other atropisomeric diphosphines such as BINAP and its pilot scale, Roche [10, 12] 1–3 pilot process, Roche [10, 12] many analogs. The nature of the PR2 group strongly influences the O catalytic performance of the metal complexes, and the ligands available COOH have different steric bulk.1 MeOBIPHEP complexes are highly effective for N α β N the hydrogenation of - and -functionalized ketones (Figure 1), the O F hydrogenation of allylic alcohols and α,β-unsaturated esters (Figure 2), COOHxNEt3 the hydrogenation of heteroarenes (Figure 3) and a variety of syntheti- Ru / p-Tol-MeOBIPHEP Ru / A101 – 60 °C, 70 bar 30 °C, 270 bar (continuous) cally useful C C coupling reactions (Figure 4). ee >99%; TON 20,000; TOF 830 h-1 ee 94%;TON 1000;TOF ~400 h-1 pilot scale, Roche [10] pilot process, Roche [10, 11] References: (1)(a) Blaser, H.U. et al. Chimica Oggi 2007, 25(2), Supplement Catalytic Applications, p 8. (b) Blaser, H.U. et al. Acc. Chem. Res. 2007, 40, 1240. (2) Tang, W.; Figure 2 Zhang, X. Chem. Rev. 2003, 103, 3029. (3) Schmid, R. et al. Pure Appl. Chem. 1996, 68, 131. (4) Ratovelomanana-Vidal, V. et al. Adv. Synth. Catal. 2003, 345, 261. (5) Blanc, D. et al. J. Organomet. Chem. 2000, 603, 128. (6) Bertus, P. et al. Tetrahedron: Asymmetry 1999, [Ir(cod)2Cl]2 / A101 10, 1369. (7) Cederbaum, F. et al. Adv. Synth. Catal. 2004, 346, 842. (8) Mordant, C. et al. R' R' Synthesis 2003, 2405. (9) Makino, K. et al. Org. Lett. 2006, 8, 4573. (10) Schmid, R.; s/c 100, 18 h [14] Scalone M. in Comprehensive Asymmetric Catalysis; Jacobsen, E. N.; Yamamoto, H.; Pfaltz, N R N R toluene, I2 H A., Eds., Springer : Berlin, 1999; p 1439. (11) Crameri, Y. et al. Chimia 1997, 51, 303. R = (subst) alkyl 80-99%, 86-96% ee (12) Netscher, T. et al. in Large Scale Asymmetric Catalysis; Blaser, H.-U.; Schmidt, E., Eds., R' = H, F, Me, MeO 50 bar, 25°C Wiley-VCH: Weinheim, 2003; p 71. (13) Bulliard, M. et al. Org. Process Res. Devel. 2001, 5, 438. (14) Wang, W-B. et al. J. Am. Chem. Soc. 2003, 125, 10536. (14) Kong, J. R.; Krische, Figure 3 M. J. J. Am. Chem. Soc. 2006, 128, 16040. (15) Han, X.; Widenhoefer, R. A. P. M. Org. Lett. 2006, 8, 3801. (16) Koh, J. H. et al. Org. Lett. 2001, 3, 1233. (17) Tschoerner, M. et al. Organometallics 1999, 18, 670. O Rh / A101 OH 2 + R [15] RR' R' DCE, Ph3CCOH, Na2SO4 1 bar, 25 °C 80%, 89% ee P P A101-1 H3CO A101-2 H3CO R R H3CO H3CO N Pt(A109)Cl N 29510 P 29511 P 2 R' AgOTf R' R" [16] "R R' R' MeOH, 25°C

OCH3 OCH3 56-96%, up to 90% ee t-Bu t-Bu t-Bu t-Bu t-Bu t-Bu O Pt / (4-tBu-Ph-MeOBIPHEP) OH OCH3 OCH3 + [17] P P H COOEt H3CO H3CO COOEt A109-1 t-Bu A109-2 t-Bu CH2Cl2, -50 °C H3CO t-Bu H3CO t-Bu 29512 P 29513 P protic additives up to 85% ee

OCH3 OCH3 t-Bu t-Bu Pd / A101 t-Bu t-Bu t-Bu t-Bu O R O R + isomer OCH3 OCH3 +ArOTf Ar [18] acetone, 40 °C >98% ee R = H, Me NEt(i-Pr)2

Figure 4

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(R)-(+)-(6,6′-Dimethoxybiphenyl-2,2′-diyl)bis(diphenylphos- (R)-(6,6′-Dimethoxybiphenyl-2,2′-diyl)bis(di-2-furyl- 8 phine), ≥97.0% (CHN) phosphine), ≥97.0% (CHN) (R)-(+)-MeO-BIPHEP; (R)-(+)-2,2′-Bis(diphenylphos- SL-A108-1; (R)-2-Furyl-MeOBIPHEP; (R)-(+)-2,2′-Bis phino)-6,6′-dimethoxy-1,1′-biphenyl; SL-A101-1 (di-2-furylphosphino)-6,6′-dimethoxy-1,1′-biphenyl O [133545‑16‑1] [145214‑57‑9] P P Solvias H CO C38H32O2P2 H3CO C30H24O6P2 3 O FW 582.61 H3CO FW 542.46 H CO P 3 P O O ® iadPortfolio Ligand 29510-100MG 100 mg 29514-100MG 100 mg 29510-500MG 500 mg 29514-500MG 500 mg 29510-1G 1g 29514-1G 1g 29510-5G 5g 29514-5G 5g

(S)-(-)-(6,6′-Dimethoxybiphenyl-2,2′-diyl)bis(diphenylphos- (S)-(6,6′-Dimethoxybiphenyl-2,2′-diyl)bis(di-2-furyl- 8 phine), ≥97.0% phosphine), ≥97.0% (CHN) (S)-(−)-2,2′-Bis(diphenylphosphino)-6,6′-dimethoxy- (S)-(−)-2,2′-Bis(di-2-furylphosphino)-6,6′-dimethoxy- 1,1′-biphenyl; (S)-(−)-MeO-BIPHEP; SL-A101-2 1,1′-biphenyl; SL-A108-2; (S)-2-Furyl-MeOBIPHEP O ‑ ‑ [145214‑59‑1] [133545 17 2] P P H CO C38H32O2P2 H3CO C30H24O6P2 3 O FW 582.61 H3CO FW 542.46 H CO P 3 P O O

29511-100MG 100 mg 29515-100MG 100 mg 29511-500MG 500 mg 29515-500MG 500 mg 29511-1G 1g 29515-1G 1g 29511-5G 5g 29515-5G 5g

(R)-(6,6′-Dimethoxybiphenyl-2,2′-diyl)bis[bis(3,5‑di-tert-bu- (R)-(6,6′-Dimethoxybiphenyl-2,2′-diyl)bis[bis(3,5- 8 tyl-4‑methoxyphenyl)phosphine], ≥97.0% (CHN) dimethylphenyl)phosphine], ≥97.0% (CHN) (R)-3,5-t-Bu-4-MeO-MeOBIPHEP; SL-A109-1; SL-A120-1; (R)-3,5-Xyl-MeOBIPHEP; (R)-2,2′-Bis OCH3 H3C CH3 ′ ′ ′ [bis(3,5-dimethyl)phosphino]-6,6′-dimethoxy- (R)-[6,6 -Dimethoxy(1,1 -biphenyl)-2,2 -diyl]bis t-Bu t-Bu CH3 {bis[3,5-bis(1,1-dimethylethyl)-4-methoxy- t-Bu 1,1′-biphenyl OCH ‑ ‑ P phenyl]phosphine} 3 [394248 45 4] H3CO CH3 ‑ ‑ P C46H48O2P2 CH [352655 61 9] H3CO t-Bu 3 FW 694.82 H3CO C74H104O6P2 H3CO t-Bu P FW 1151.56 P CH3 OCH3 t-Bu H3C CH3 t-Bu t-Bu

OCH3 29516-100MG 100 mg 29516-500MG 500 mg 29512-100MG 100 mg 29516-1G 1g 29512-500MG 500 mg 29516-5G 5g 29512-1G 1g 29512-5G 5g (S)-(6,6′-Dimethoxybiphenyl-2,2′-diyl)bis[bis(3,5- 8 dimethylphenyl)phosphine], ≥97.0% (CHN) (S)-(6,6′-Dimethoxybiphenyl-2,2′-diyl)bis[bis(3,5‑di-tert-bu- ‑ ≥ (S)-3,5-Xyl-MeOBIPHEP; SL-A120-2; (S)-2,2′-Bis tyl-4 methoxyphenyl)phosphine], 97.0% (CHN) H3C CH3 [bis(3,5-dimethyl)phosphino]-6,6′-dimethoxy- SL-A109-2; (S)-3,5-t-Bu-4-MeO-MeOBIPHEP; CH3 OCH3 ′ ′ ′ ′ 1,1 -biphenyl (S)-[6,6 -Dimethoxy(1,1 -biphenyl)-2,2 -diyl]bis t-Bu t-Bu ‑ ‑ P t-Bu [362634 22 8] H3CO {bis[3,5-bis(1,1-dimethylethyl)-4-methoxy- CH3 C46H48O2P2 CH OCH3 3 phenyl]phosphine} FW 694.82 H3CO P P C74H104O6P2 H3CO t-Bu FW 1151.56 H CO t-Bu CH3 3 P H3C CH3 OCH3 t-Bu t-Bu t-Bu 29517-100MG 100 mg OCH3 29517-500MG 500 mg 29517-1G 1g 29513-100MG 100 mg 29517-5G 5g 29513-500MG 500 mg 29513-1G 1g 29513-5G 5g

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(R)-(6,6′-Dimethoxybiphenyl-2,2′-diyl)bis(diisopropyl- 8 (R)-(6,6′-Dimethoxybiphenyl-2,2′-diyl)bis[bis(3,5-di- 8 phosphine), ≥97.0% (CHN) tert-butylphenyl)phosphine], ≥97.0% (CHN) SL-A116-1; (R)-iPr-MeOBIPHEP; (R)-2,2′-Bis(diisopro- SL-A121-1; (R)-3,5-t-Bu-MeOBIPHEP; (R)-2,2′-Bis H3C CH3 t-Bu t-Bu pylphosphino)-6,6′-dimethoxy-1,1′-biphenyl [bis(3,5-di-tert-butyl)phosphino]-6,6′-dimethoxy- CH3 t-Bu ‑ ‑ P ′ [150971 45 2] H CO 1,1 -biphenyl 3 CH3 P C26H40O2P2 [192138‑05‑9] H3CO H CO CH3 FW 446.54 3 P C70H96O2P2 t-Bu CH3 FW 1031.46 t-Bu

H3CCH3 H CO 3 P

t-Bu 29518-100MG 100 mg t-Bu t-Bu 29518-500MG 500 mg 29518-1G 1g 29524-100MG 100 mg 29518-5G 5g 29524-500MG 500 mg Ligand Portfolio 29524-1G 1g ® (S)-(6,6′-Dimethoxybiphenyl-2,2′-diyl)bis(diisopropyl- 8 29524-5G 5g phosphine), ≥97.0% (CHN) SL-A116-2; (S)-iPr-MeOBIPHEP; (S)-2,2′-Bis(diisopro- 8 H3C CH3 (S)-(6,6′-Dimethoxybiphenyl-2,2′-diyl)bis[bis(3,5-di- pylphosphino)-6,6′-dimethoxy-1,1′-biphenyl ≥ CH3 tert-butylphenyl)phosphine], 97.0% (CHN) Solvias ‑ ‑ P [150971 43 0] H CO 3 CH3 SL-A121-2; (S)-3,5-t-Bu-MeOBIPHEP; (S)-2,2′-Bis C26H40O2P2 t-Bu t-Bu H CO CH3 ′ FW 446.54 3 P [bis(3,5-di-tert-butyl)phosphino]-6,6 - t-Bu CH3 dimethoxy-1,1'-biphenyl ‑ ‑ P H3CCH3 [167709 31 1] H3CO t-Bu C70H96O2P2 t-Bu FW 1031.46 H3CO 29519-100MG 100 mg P

29519-500MG 500 mg t-Bu

29519-1G 1g t-Bu t-Bu 29519-5G 5g 29525-100MG 100 mg (R)-(6,6′-Dimethoxybiphenyl-2,2′-diyl)bis[bis(4- 8 29525-500MG 500 mg methylphenyl)phosphine], ≥97.0% (CHN) 29525-1G 1g (R)-p-Tol-MeOBIPHEP; SL-A102-1; (R)-2,2′-Bis(di- 29525-5G 5g CH3 p-tolylphosphino)-6,6′-dimethoxy-1,1′-biphenyl [133545‑24‑1] (R)-(6,6′-Dimethoxybiphenyl-2,2′-diyl)bis[bis(3,4,5-tri- 8 C42H40O2P2 methoxyphenyl)phosphine], ≥97.0% (CHN) P CH3 FW 638.71 H CO 3 (R)-3,4,5-MeO-MeOBIPHEP; SL-A104-1; (R)- H CO OCH3 3 P CH ′ 3 2,2 -Bis[bis(3,4,5-trimethoxyphenyl) H3CO OCH3 ′ ′ phosphino]-6,6 -dimethoxy-1,1 -biphenyl OCH3 [256390‑47‑3] P OCH3 C50H56O14P2 H3CO CH3 OCH3 FW 942.92 OCH3 H3CO P OCH3 29520-100MG 100 mg 29520-500MG 500 mg OCH3 29520-1G 1g H3CO OCH3 OCH3 29520-5G 5g

29526-100MG 100 mg (S)-(6,6′-Dimethoxybiphenyl-2,2′-diyl)bis[bis(4-methyl- 8 29526-500MG 500 mg phenyl)phosphine], ≥97.0% (CHN) 29526-1G 1g SL-A102-2; (S)-p-Tol-MeOBIPHEP; (S)-2,2′-Bis(di- CH3 29526-5G 5g p-tolylphosphino)-6,6′-dimethoxy-1,1′-biphenyl [133545‑25‑2] C42H40O2P2 P CH3 FW 638.71 H3CO

H3CO P CH3

CH3

29521-100MG 100 mg 29521-500MG 500 mg 29521-1G 1g 29521-5G 5g

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(S)-(6,6′-Dimethoxybiphenyl-2,2′-diyl)bis[bis(3,4,5-tri- 8 Josiphos methoxyphenyl)phosphine], ≥97.0% (CHN) The Josiphos ligands arguably constitute one of the most versatile and ′ SL-A104-2; (S)-2,2 -Bis[bis(3,4,5-trimethoxy- OCH successful ligand families, second probably only to the BINAP ligands. ′ ′ 3 phenyl)phosphino]-6,6 -dimethoxy-1,1 - H3CO OCH3 Since the two phosphine groups are introduced in consecutive steps with 1,2 biphenyl; (S)-3,4,5-MeO-MeOBIPHEP OCH3 very high yields, a variety of ligands are readily available with widely Solvias [927396‑01‑8] differing steric and electronic properties. Up to now, only the P OCH3 C50H56O14P2 H3CO (R,SFc)-family (and its enantiomers) but not the (R,RFc) diastereomers have OCH3 FW 942.92 OCH3 led to high enantioselectivities. At present, about 150 different Josiphos H3CO P OCH3 ligands have been prepared and 40 derivatives are available in a ligand 3 kit (12000) for screening and on a multikilogram scale for production. ® OCH3 iadPortfolio Ligand H CO OCH Catalytic applications of the Josiphos ligand family were reviewed up to 3 3 3 OCH3 2002. Until now, Josiphos ligands have been applied in 4 production processes and about 5 or 6 pilot and bench scale processes involving Rh, Ir, and Ru catalyzed hydrogenation reactions of C=C and C=N bonds.4 29527-100MG 100 mg Selected applications are summarized in Figure 1. The most important 500 mg 29527-500MG application is undoubtedly the Ir/J005‑1 catalyzed hydrogenation of a 29527-1G 1g hindered N-aryl imine of methoxyacetone, the largest known 29527-5G 5g enantioselective process operated for the enantioselective production of the herbicide (S)-metolachlor.2,5 The hydrogenation of tetrasubstituted (R)-(6,6′-Dimethoxybiphenyl-2,2′-diyl)bis{bis[3,5-diiso- 8 olefins was the key step for two production processes developed for the ≥ synthesis of biotin by Lonza and of methyl dihydrojasmonate by propyl-4-(dimethylamino)phenyl]phosphine}, 97.0% 6 (CHN) Firmenich. Pilot processes were developed by Lonza for a building block of crixivan and for dextromethorphane.6 Recently, MSD Sharp & Dome (R)-2,2′-Bis[bis(3,5-diisopropyl-4-dimethyl- chemists reported the unprecedented hydrogenation of H3C CH3 GmbH aminophenyl)phosphino]-6,6′-dimethoxy-1,1′- N unprotected dehydro β-amino acid derivatives catalyzed by Rh-Josiphos i-Pr i-Pr biphenyl; (R)-3,5-iPr-4-NMe2-MeOBIPHEP; SL- with ee's up to 97%. It was shown that not only simple derivatives but i-Pr A107-1 also the complex intermediate for MK-0431 depicted in Figure 1 can be ‑ ‑ P hydrogenated successfully. Regular production on a multiton/year scale [352655 40 4] H CO 3 with ee's up to 98% has been started in 2006.7 C70H100N4O2P2 i-Pr FW 1091.52 i-Pr Rh and Ir complexes with chiral Josiphos ligands are highly selective, CH3 H3CO active, and productive catalysts for various enantioselective reductions. P N Very high enantioselectivities were described for the enantioselective CH3 i-Pr hydrogenation of enamides, itaconic acid derivatives, acetoacetates as i-Pr i-Pr well as N-aryl imines (in presence of acid and iodide) and 3 N phosphinylimines. Josiphos J001 is the ligand of choice for the H3C CH3 Cu catalyzed reduction of activated C=C bonds with polymethylhydrosiloxane (PMHS) (Figure 2) with very high 29528-100MG 100 mg enantioselectivities for nitro alkenes,8 α,β-unsaturated ketones,9a 29528-500MG 500 mg esters,9b,c and nitriles.10 Very recently, it was disclosed that Ru-Josiphos- 29528-1G 1g pyridinyl-alkylamines complexes (best ligands J001 and J007) are 29528-5G 5g extraordinarily effective for the enantioselective transfer hydrogenation of aryl ketones with turnover frequencies for full conversion exceeding 20,000 h-1 (Figure 3).11 (S)-(6,6′-Dimethoxybiphenyl-2,2′-diyl)bis{bis[3,5-diiso- 8 propyl-4-(dimethylamino)phenyl]phosphine}, ≥97.0% Josiphos complexes have been successfully applied to various asymmetric catalytic coupling reactions such as allylic alkylation or (CHN) hydroformylation.3 Selected recent examples are depicted in Figure 4. SL-A107-2; (S)-3,5-iPr-4-NMe -MeOBIPHEP; Feringa's group reported high ee's for the Cu catalyzed Michael addition 2 H3C CH3 (S)-2,2′-Bis[bis(3,5-diisopropyl-4-dimethyl- N of Grignard reagents to α,β-unsaturated esters,12a thioesters,12b,c and i-Pr i-Pr aminophenyl)phosphino]-6,6′-dimethoxy-1,1′- for selected cyclic enones.12d The preferred ligands were J001 and J004. i-Pr biphenyl The Rh/J001 was very effective for the nucleophilic ring opening of [352655‑40‑4] P various oxabicyclic substrates leading to interesting new tetrahydro- H3CO 13a,b C70H100N4O2P2 naphthalene and cyclohexene derivatives. This reaction was scaled i-Pr 13c FW 1091.52 i-Pr up to the kilogram scale. The Pd catalyzed opening of various cyclic CH3 anhydrides with Ph2Zn was described by Bercot and Rovis to occur with H3CO P N very high ee's in presence of J001.14 Lorman et al.15 reported up to 95% CH3 i-Pr ee for an intermolecular Heck reaction using a Pd/J001 catalyst. i-Pr i-Pr Josiphos ligands were not only applied to enantioselective reactions but N H3C CH3 also were shown to be useful for Pd catalyzed coupling reactions with very high activities. Hartwig's group reported that Pd/J009 (88733 and 29529-100MG 100 mg 88734) complexes were effective catalysts for the amination of aryl halides or sulfonates with ammonia,16a coupling of aryl halides or 29529-500MG 500 mg sulfonates with thiols,16b and Kumada coupling of aryl or vinyl tosylates 29529-1G 1g with Grignard reagents.16c 29529-5G 5g References: (1) Togni, A. et al. J. Am. Chem. Soc. 1994, 116, 4062. (2) For a scalable synthesis of Ugi amine see Blaser, H. U. et al. Chimia 1999, 53, 275. (3) Blaser, H. U. et al. Topics in Catalysis 2002, 19, 3. (4) Blaser, H. U. et al. in Handbook of Homogeneous Hydrogenation; de Vries, J. G.; Elsevier, C.J., eds., Wiley-VCH, 2007; p 1279. (5) Blaser, H. U. Adv. Synth. Catal. 2002, 344, 17. (6) For details see ref. 3. (7)(a) Rouhi, M. C&EN, 2004, 82(37), 28. (b) Hsiao, Y. et al. J. Am. Chem. Soc. 2004, 126, 9918; (c) Kubryk, M.; Hansen, K. B. Tetrahedron: Asymmetry 2006, 17, 205; (d) Clausen, A. M. et al. Org. Process Res. Devel. 2006, 10, 723. (8)(a) Czekelius, C.; Carreira, E. M. Angew. Chem., Int. Ed. 2003, 42, 4793. (b) Czekelius, C.; Carreira, E. M. Org. Lett. 2004, 6, 4575. (9)(a) Lipshutz, B. H. Servesko, J. M. Angew. Chem., Int. Ed. 2003, 42, 4789. (b) Lipshutz, B. H. et al. J. Am. Chem. Soc. 2004, 126, 8352. (c) Lipshutz, B. H. et al. Org. Lett. 2006, 8, 1963. (10) Lee, D. et al. Angew. Chem., Int. Ed. 2006, 45, 2785. (11) Baratta, W.; et al. Angew., Chem., Int. Ed. 2007, 46, 7651. (12)(a) Lopez, F. et al. Angew. Chem.; Int. Ed. 2005, 44, 2752.

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NH (b) Des Mazery, R. M. et al. J. Am. Chem. Soc. 2005, 127, 9966. (c) Howell, G. P. et al. 0.05 mol% OH 2 O N J. Am. Chem. Soc. 2006, 128, 14977. (d) Feringa, B. L. et al. Proc. N. Y. Acad. Sci. 2004, Ru(Josiphos, RPyme)Cl2 R' R R' R [11] 101, 5834. (13)(a) Lautens, M. K. et al. Acc. Chem. Res. 2003, 36, 48; (b) Lautens, M.; R Fagnou, K. Proc. N. Y. Acad. Sci. , 101, 5455. (c) Solvias AG, unpublished results. i-PrOH / i-PrOK 2004 60 °C, 5-30 min (14) Bercot, E. A.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 10248. (15) Lormann, M. E. P. 95 - >99% ee RPyme et al. J. Organomet. Chem. 2006, 691, 2159. (16)(a) Shen, Q.; Hartwig, J. F. J. Am. Chem. 95 - 99% cv Soc. 2006, 128, 10028. (b) Fernandez-Rodriguez, M. A. Q. et al. J. Am. Chem. Soc. 2006, 128, 2180. (c) Limmert, M. E. et al. J. Org. Chem. 2005, 70, 9364. Figure 3

0.5 - 2.5 mol% R' [25a] H3C COOMe Cu / Josiphos COOMe J001-1 J001-2 P R + R'MgBr R P t-BuOMe P 88717 Fe 88718 P -75 °C, 1-2 h 75-99% CH3 86-97% ee Fe

R O R + H3C NuH Rh/J001 [27] Ligand Portfolio CH3 Nu H3C CH 3 OH

® THF, 80 °C J002-1 P CH3 J004-1 P P CH P NuH = ROH, N-nucleophiles Fe 3 Fe 93 - >99% ee 88719 CH3 88723 CH3

O H O H R R 5% Pd/J001 Ph CH3 [28] H3C O + Ph2Zn Solvias CH3 R THF, 80 °C R COOH J004-2 J005-1 H O H P P P cyclic and acyclic 70-95% 88724 Fe 88725 P H3C up to 97% ee Fe CH3 CH3 CN X = I, Br, OTf CN 10% Pd/J001 [30] CH3 H3C OCH3 H3CO X DMF, 65-90 °C O CH3 O H C 3 P P J007-1 P J007-2 Fe P 88729 CH3 88730 H3C Fe 80-92% CH3 60-94% ee H3C CH H CO 3 H3C OCH3 3 Figure 4

H3CO CH3 H3C CH3 H3C H3C CH J013-1 P 3 P CH3 (R)-1-[(S )-2-(Diphenylphosphino)ferrocenyl]ethyldicyclo- Fe CH3 P 88737 CH3 H3C hexylphosphine H3CO CH3 (R)-(S)-Josiphos; (2R)-1-[(1R)-1-(Dicyclohexyl- phosphino)ethyl]-2-(diphenylphosphino)

H3CO ferrocene (acc to CAS); Josiphos SL-J001-1 H P O [155806‑35‑2] COOMe P Fe N N NH C36H44FeP2 ·C2H5OH CH3 FW 640.60

O O O ≥97.0% (CHN) Ir / J005-1; 80% ee Rh / J002-1; 99% de Ru / J001-1; 90% ee 88717-100MG 100 mg TON 2,000,000; TOF > 400,000 h-1 TON 2000; TOF n.a. TON 2000; TOF 200 h-1 medium scale production very large scale production medium scale production 88717-500MG 500 mg Lonza [6] Ciba-Geigy/Solvias [2,5] Firmenich [6] CF3 88717-1G 1g F N O N . H PO N 88717-5G 5g 3 4 N N N N O NH2 O OHC F (S)-1-[(RP)-2-(Diphenylphosphino)ferrocenyl]ethyldicyclo- NHtBu O F M hexylphosphine e Rh / J002-1; 97% ee Ir / J013-1; 90% ee Rh / J002-1, 94% ee TON 1000; TOF 450 h-1 TON 1500; TOF n.a. TON 350; TOF ~50 h-1 (S)-(R)-Josiphos; (2S)-1-[(1S)-1-(Dicyclohexyl- pilot process pilot process, >200 kg multi tons/year Lonza [6] phosphino)ethyl]-2-(diphenylphosphino) Lonza [6] MSD Sharp & Dome GmbH [7] ferrocene (acc to CAS); Josiphos SL-J001-2 H [162291‑02‑3] P Figure 1 Fe P C36H44FeP2 ·C2H5OH CH3 FW 640.60

0.1 - 3 mol% ≥97.0% (CHN) R Cu / J001 R X + PMHS X [8-10] 88718-100MG 100 mg R' R' toluene 88718-500MG 500 mg X = NO2, COMe, CN 80 - 99% ee 60 - >90% 88718-1G 1g 88718-5G 5g Figure 2

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(R)-1-[(SP)-2-(Diphenylphosphino)ferrocenyl]ethyldi-tert- (R)-1-[(SP)-2-(Dicyclohexylphosphino)ferrocenylethyl] butylphosphine, ≥97.0% (CHN) diphenylphosphine (2R)-1-[(1R)-1-[Bis(1,1-dimethylethyl) (1R)-1-(Dicyclohexylphosphino)-2-[(1R)-1- H3C phosphino]ethyl]-2-(diphenylphosphino) H3C CH3 (diphenylphosphino)ethyl]ferrocene (acc to H CH ferrocene (acc to CAS); Josiphos SL-J002-1 P 3 CAS); Josiphos SL-J004-1 H CH P Solvias [155830‑69‑6] P Fe 3 [158923‑09‑2] CH P Fe CH3 3 C32H40FeP2 C36H44FeP2 CH3 FW 542.45 FW 594.53

88719-100MG 100 mg ≥97.0% (CHN) ®

88719-500MG 500 mg 88723-100MG 100 mg Portfolio Ligand 88719-1G 1g 88723-500MG 500 mg 88719-5G 5g 88723-1G 1g 88723-5G 5g (S)-1-[(RP)-2-(Diphenylphosphino)ferrocenyl]ethyldi-tert- ≥ butylphosphine, 97.0% (CHN) (S)-1-[(RP)-2-(Dicyclohexylphosphino)ferrocenyl]ethyl- (2S)-1-[(1S)-1-[Bis(1,1-dimethylethyl) diphenylphosphine, ≥97.0% (CHN) CH3 H C phosphino]ethyl]-2-(diphenylphosphino) 3 CH3 (1S)-1-(Dicyclohexylphosphino)-2-[(1S)-1- H C H ferrocene (acc to CAS); Josiphos SL-J002-2 3 P (diphenylphosphino)ethyl]ferrocene (acc to [277306‑29‑3] H3C Fe P CAS); Josiphos SL-J004-2 H H3C CH3 P C32H40FeP2 [162291‑01‑2] FW 542.45 Fe P C36H44FeP2 CH3 FW 594.53 88720-100MG 100 mg 88720-500MG 500 mg 88724-100MG 100 mg 88720-1G 1g 88724-500MG 500 mg 88720-5G 5g 88724-1G 1g 88724-5G 5g (R)-1-[(SP)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldicyclohexylphosphine, ≥97.0% (CHN) (R)-1-[(SP)-2-(Diphenylphosphino)ferrocenyl]ethyldi(3,5‑xyl- (1R)-1-(Dicyclohexylphosphino)-2-[(1R)-1- yl)phosphine, ≥97.0% (CHN) (dicyclohexylphosphino)ethyl]ferrocene (acc to H3C CH3 CAS); Josiphos SL-J003-1 H ‑ ‑ P [167416 28 6] P Fe C36H56FeP2 CH3 H P CH3 FW 606.62 P Fe CH3 88721-100MG 100 mg CH3 88721-500MG 500 mg (2R)-1-[(1R)-1-[Bis(3,5‑dimethylphenyl)phosphino]ethyl]-2-(diphenylphos- 88721-1G 1g phino)ferrocene (acc to CAS); Josiphos SL-J005‑1 88721-5G 5g [184095‑69‑0] C40H40FeP2 (S)-1-[(RP)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldicyclo- FW 638.54 hexylphosphine, ≥97.0% (CHN) 88725-100MG 100 mg (1S)-1-(Dicyclohexylphosphino)-2-[(1S)-1- 88725-500MG 500 mg (dicyclohexylphosphino)ethyl]ferrocene (acc to 88725-1G 1g

CAS); Josiphos SL-J003-2 H 88725-5G 5g [246231‑77‑6] P Fe P C36H56FeP2 CH3 (S)-1-[(RP)-2-(Diphenylphosphino)ferrocenyl]ethyldi(3,5‑xyl- FW 606.62 yl)phosphine, ≥97.0% (CHN)

88722-100MG 100 mg H3C CH3 88722-500MG 500 mg H 88722-1G 1g H3C P 88722-5G 5g Fe P CH3

CH3

(2S)-1-[(1S)-1-[Bis(3,5‑dimethylphenyl)phosphino]ethyl]-2-(diphenylphosphino)ferrocene (acc to CAS); Josiphos SL-J005‑2 [223121‑07‑1] C40H40FeP2 FW 638.54 88726-100MG 100 mg 88726-500MG 500 mg 88726-1G 1g 88726-5G 5g

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(R)-1-{(SP)-2-[Bis[3,5‑bis(trifluoromethyl)phenyl]phosphino] (S)-1-{(RP)-2-[Bis(4‑methoxy-3,5‑dimethylphenyl)phosphino] ferrocenyl}ethyldicyclohexylphosphine, ≥97.0% (19F-NMR) ferrocenyl}ethyldicyclohexylphosphine, ≥97.0% (CHN)

CF3 CH3 OCH3 H H P P F C 3 P Fe CH Fe P 3 F3C CH CH 3 3 CH3

OCH3 CF3 CH3 ‑ (1R)-1-[Bis[3,5 bis(trifluoromethyl)phenyl]phosphino]-2-[(1R)-1-(dicyclo- (1S)-1-[Bis(4‑methoxy-3,5‑dimethylphenyl)phosphino]-2-[(1S)-1-(dicyclo- ‑ hexylphosphino)ethyl]ferrocene (acc to CAS); Josiphos SL-J006 1 hexylphosphino)ethyl]ferrocene (acc to CAS); Josiphos SL-J007‑2 ‑ ‑ [292638 88 1] [849923‑88‑2] C40H40F12FeP2 C H FeO P FW 866.52 42 56 2 2 Ligand Portfolio FW 710.69

® 88727-100MG 100 mg 88730-100MG 100 mg 88727-500MG 500 mg 88730-500MG 500 mg 88727-1G 1g 88730-1G 1g 88727-5G 5g 88730-5G 5g Solvias ‑ (S)-1-{(RP)-2-[Bis[3,5 bis(trifluoromethyl)phenyl]phosphino]- (R)-1-{(S )-2-[Bis[3,5‑bis(trifluoromethyl)phenyl]phosphino] ≥ 19 P ferrocenyl}ethyldicyclohexylphosphine, 97.0% ( F-NMR) ferrocenyl}ethyldi(3,5‑xylyl)phosphine

H C CH CF 3 3 3 CF3 H P H P CH CF 3 Fe P 3 F3C CH P Fe 3 CF3 F C 3 CH3

CH3 CF 3 CF3

(1S)-1-[Bis[3,5‑bis(trifluoromethyl)phenyl]phosphino]-2-[(1S)-1-(dicyclo- (1R)-1-[Bis[3,5‑bis(trifluoromethyl)phenyl]phosphino]-2-[(1R)-1-[bis hexylphosphino)ethyl]ferrocene (acc to CAS); Josiphos SL-J006‑2 (3,5‑dimethylphenyl)phosphino]ethyl]ferrocene (acc to CAS); Josiphos [849923‑15‑5] SL-J008‑1 C40H40F12FeP2 [166172‑63‑0] FW 866.52 C44H36F12FeP2 88728-100MG 100 mg FW 910.53 19 88728-500MG 500 mg ≥97.0% ( F-NMR) 88728-1G 1g 88731-100MG 100 mg 88728-5G 5g 88731-500MG 500 mg 88731-1G 1g (R)-1-{(SP)-2-[Bis(4‑methoxy-3,5‑dimethylphenyl)phosphino] 88731-5G 5g ferrocenyl}ethyldicyclohexylphosphine, ≥97.0% (CHN)

(S)-1-{(RP)-2-[Bis[3,5‑bis(trifluoromethyl)phenyl]phosphino] 19 CH3 ferrocenyl}ethyldi(3,5‑xylyl)phosphine, ≥97.0% ( F-NMR) H3CO H P H3C CH3 H C 3 P Fe CF H C 3 3 CH3 H H3C P H3CO CF Fe P 3 CH3 CH 3 CF3

CH3 (1R)-1-[Bis(4‑methoxy-3,5‑dimethylphenyl)phosphino]-2-[(1R)-1-(dicyclohexylphosphino)ethyl]ferrocene (acc to CAS); Josiphos SL-J007‑1 CF3 [360048‑63‑1] ‑ C42H56FeO2P2 (1S)-1-[Bis[3,5 bis(trifluoromethyl)phenyl]phosphino]-2-[(1S)-1-[bis FW 710.69 (3,5‑dimethylphenyl)phosphino]ethyl]ferrocene (acc to CAS); Josiphos ‑ 88729-100MG 100 mg SL-J008 2 C H F FeP 88729-500MG 500 mg 44 36 12 2 FW 910.53 88729-1G 1g 88732-100MG 100 mg 88729-5G 5g 88732-500MG 500 mg 88732-1G 1g 88732-5G 5g

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(R)-1-[(SP)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldi-tert- (R)-1-[(SP)-2-[Bis(4‑methoxy-3,5‑dimethylphenyl)phosphino] butylphosphine, ≥97.0% (CHN) ferrocenyl}ethyldi-tert-butylphosphine, ≥97.0% (CHN) (2R)-1-[(1R)-1-[Bis(1,1-dimethylethyl) H3C CH3 H3C CH CH phosphino]ethyl]-2-(dicyclohexylphosphino) H3C 3 H3CO H3C 3 H CH H CH ferrocene (acc to CAS); Josiphos SL-J009-1 P 3 3

P Solvias CH H C CH ‑ ‑ P Fe 3 3 P Fe 3 [158923 11 6] H C CH CH3 3 CH CH3 C32H52FeP2 3 3

FW 554.55 H3CO CH3

88733-100MG 100 mg ®

88733-500MG 500 mg (2R)-1-[(1R)-1-[Bis(1,1‑dimethylethyl)phosphino]ethyl]-2-[bis(4‑methoxy- Portfolio Ligand ‑ 88733-1G 1g 3,5 dimethylphenyl)phosphino]ferrocene (acc to CAS); Josiphos SL- ‑ 88733-5G 5g J013 1 [187733‑50‑2] C38H52FeO2P2 (S)-1-[(RP)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldi-tert- FW 658.61 butylphosphine, ≥97.0% (CHN) 88737-100MG 100 mg (2S)-1-[(1S)-1-[Bis(1,1-dimethylethyl) CH3 88737-500MG 500 mg H3C CH phosphino]ethyl]-2-(dicyclohexylphosphino) 3 88737-1G 1g ferrocene (acc to CAS); Josiphos SL-J009-2 H3C H P 88737-5G 5g H3C C32H52FeP2 Fe P FW 554.55 H3C CH3 (S)-1-[(RP)-2-[Bis(4‑methoxy-3,5‑dimethylphenyl)phosphino] ferrocenyl}ethyldi-tert-butylphosphine, ≥97.0% (CHN) 88734-100MG 100 mg CH3 CH3 88734-500MG 500 mg H C 3 CH3 OCH3 H C H 88734-1G 1g 3 P H3C CH 88734-5G 5g Fe P 3 H3C CH3 CH3

OCH (R)-1-{(SP)-2-[Bis[4-(trifluoromethyl)phenyl]phosphino]ferro- 3 cenyl}ethyldi-tert-butylphosphine, ≥97.0% (19F-NMR) CH3 (2S)-1-[(1S)-1-[Bis(1,1‑dimethylethyl)phosphino]ethyl]-2-[bis(4‑methoxy- H3C H C CH3 ‑ F3C 3 3,5 dimethylphenyl)phosphino]ferrocene (acc to CAS); Josiphos SL- H CH ‑ P 3 J013 2 CH P Fe 3 [849924‑40‑9] CH CH3 3 C38H52FeO2P2

F3C FW 658.61 88738-100MG 100 mg (2R)-1-[(1R)-1-[Bis(1,1‑dimethylethyl)phosphino]ethyl]-2-[bis[4-(trifluoro- 88738-500MG 500 mg methyl)phenyl]phosphino]ferrocene (acc to CAS); Josiphos SL-J011‑1 88738-1G 1g [246231‑79‑8] 88738-5G 5g C34H38F6FeP2 FW 678.45 88735-100MG 100 mg (R)-1-{(SP)-2-[Di(2‑furyl)phosphino]ferrocenyl}ethyldi(3,5‑xyl- ≥ 88735-500MG 500 mg yl)phosphine, 97.0% (CHN) 88735-1G 1g H3C CH3 88735-5G 5g

H P CH3 (S)-1-{(RP)-2-[Bis[4-(trifluoromethyl)phenyl]phosphino]ferro- O P Fe 19 cenyl}ethyldi-tert-butylphosphine, ≥97.0% ( F-NMR) CH3 O CH3

CH3 H3C CH3 CF3 (2R)-1-[(1R)-1-[Bis(3,5‑dimethylphenyl)phosphino]ethyl]-2-(di-2‑furanyl- H C H 3 P phosphino)ferrocene (acc to CAS); Josiphos SL-J015‑1 H3C Fe P ‑ ‑ H3C CH3 [649559 65 9] C36H36FeO2P2 CF3 FW 618.46 88739-100MG 100 mg (2S)-1-[(1S)-1-[Bis(1,1‑dimethylethyl)phosphino]ethyl]-2-[bis[4-(trifluoromethyl)phenyl]phosphino]ferrocene (acc to CAS); Josiphos SL-J011‑2 88739-500MG 500 mg [849924‑37‑4] 88739-1G 1g C34H38F6FeP2 88739-5G 5g FW 678.45 88736-100MG 100 mg 88736-500MG 500 mg 88736-1G 1g 88736-5G 5g

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(S)-1-{(RP)-2-[Di(2‑furyl)phosphino]ferrocenyl}ethyldi(3,5‑xyl- (S)-1-{(RP)-2-[Di(1‑naphthyl)phosphino]ferrocenyl}ethyldi- yl)phosphine, ≥97.0% (CHN) tert-butylphosphine, ≥97.0% (CHN)

H C CH 3 3 CH3 H3C CH3 H C H H 3 P H C P H C 3 3 Fe P Fe O H C P 3 CH3 H3C O CH3 ‑ ‑ (2S)-1-[(1S)-1-[Bis(3,5‑dimethylphenyl)phosphino]ethyl]-2-(di-2‑furanyl- (2S)-1-[(1S)-1-[Bis(1,1 dimethylethyl)phosphino]ethyl]-2-(di-1 naph- ‑ phosphino)ferrocene (acc to CAS); Josiphos SL-J015‑2 thalenylphosphino)ferrocene (acc to CAS); Josiphos SL-J216 2 ‑ ‑ [649559‑66‑0] [849924 44 3] C40H44FeP2 C36H36FeO2P2 FW 618.46 FW 642.57 88744-100MG 100 mg

Ligand Portfolio 88740-100MG 100 mg 88744-500MG 500 mg

® 88740-500MG 500 mg 88744-1G 1g 88740-1G 1g 88744-5G 5g 88740-5G 5g ‑

Solvias ‑ (R)-1-{(SP)-2-[Di(1 naphthyl)phosphino]ferrocenyl}ethyldi (R)-1-{(SP)-2-[Di(2 furyl)phosphino]ferrocenyl}ethyldi-tert- ‑ ≥ butylphosphine, ≥97.0% (CHN) (3,5 xylyl)phosphine, 97.0% (CHN)

(2R)-1-[(1R)-1-[Bis(1,1-dimethylethyl) H3C CH3 H3C phosphino]ethyl]-2-(di-2-furanylphosphino) H3C CH3 H CH ferrocene (acc to CAS); Josiphos SL-J212-1 P 3 H P CH3 O CH3 [849924‑41‑0] P Fe P Fe CH CH3 C H FeO P 3 CH3 28 36 2 2 O FW 522.38 CH3

88741-100MG 100 mg (2R)-1-[(1R)-1-[Bis(3,5‑dimethylphenyl)phosphino]ethyl]-2-(di-1‑naph- 88741-500MG 500 mg thalenylphosphino)ferrocene (acc to CAS); Josiphos SL-J404‑1 88741-1G 1g [851308‑40‑2] 88741-5G 5g C48H44FeP2 FW 738.66 88745-100MG 100 mg (S)-1-{(RP)-2-[Di(2‑furyl)phosphino]ferrocenyl}ethyldi-tert- butylphosphine, ≥97.0% (CHN) 88745-500MG 500 mg (2S)-1-[(1S)-1-[Bis(1,1-dimethylethyl) 88745-1G 1g CH3 88745-5G 5g phosphino]ethyl]-2-(di-2-furanylphosphino) H3C CH3 H C H ferrocene (acc to CAS); Josiphos SL-J212-2 3 P H3C O [849924‑42‑1] Fe P (S)-1-{(RP)-2-[Di(1‑naphthyl)phosphino]ferrocenyl}ethyldi H C C H FeO P 3 H3C ‑ ≥ 28 36 2 2 O (3,5 xylyl)phosphine, 97.0% (CHN) FW 522.38 H3C CH3 88742-100MG 100 mg

88742-500MG 500 mg H H3C P 88742-1G 1g Fe P 88742-5G 5g H3C CH3 (R)-1-{(S )-2-[Di(1‑naphthyl)phosphino]ferrocenyl}ethyldi- P (2S)-1-[(1S)-1-[Bis(3,5‑dimethylphenyl)phosphino]ethyl]-2-(di-1‑naph- tert-butylphosphine, ≥97.0% (CHN) thalenylphosphino)ferrocene (acc to CAS); Josiphos SL-J404‑2 [851308‑41‑3] H3C H3C CH3 C48H44FeP2 H CH FW 738.66 P 3 CH P Fe 3 88746-100MG 100 mg CH CH3 3 88746-500MG 500 mg 88746-1G 1g (2R)-1-[(1R)-1-[Bis(1,1‑dimethylethyl)phosphino]ethyl]-2-(di-1‑naph- 88746-5G 5g thalenylphosphino)ferrocene (acc to CAS); Josiphos SL-J216‑1 [849924‑43‑2] C40H44FeP2 FW 642.57 88743-100MG 100 mg 88743-500MG 500 mg 88743-1G 1g 88743-5G 5g

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(R)-1-{(SP)-2-[Bis(4‑methoxy-3,5‑dimethylphenyl)phosphino] (S)-1-{(RP)-2-[Bis(4‑methoxy-3,5‑dimethylphenyl)phosphino] ferrocenyl}-ethyldi(3,5‑xylyl)phosphine, ≥97.0% (CHN) ferrocenyl}-ethylbis(2‑methylphenyl)phosphine, ≥97.0% (CHN) H3C CH3 CH3 H3CO CH3

H CH OCH3 Solvias P CH3 CH3 3 H C H 3 P Fe P H C CH 3 CH3 Fe P 3 CH H3C 3 CH3 H3CO CH3 OCH3 ® CH3 iadPortfolio Ligand (2R)-1-[(1R)-1-[Bis(3,5‑dimethylphenyl)phosphino]ethyl]-2-[bis (4‑methoxy-3,5‑dimethylphenyl)phosphino]ferrocene (acc to CAS); (1S)-1-[Bis(4‑methoxy-3,5‑dimethylphenyl)phosphino]-2-[(1S)-1-[bis Josiphos SL-J418‑1 (2‑methylphenyl)phosphino]ethyl]ferrocene (acc to CAS); Josiphos SL- [849924‑45‑4] J425‑2 ‑ ‑ C46H52FeO2P2 [849924 52 3] FW 754.70 C44H48FeO2P2 FW 726.64 88747-100MG 100 mg 88750-100MG 100 mg 88747-500MG 500 mg 88750-500MG 500 mg 88747-1G 1g 88750-1G 1g 88747-5G 5g 88750-5G 5g (S)-1-{(R )-2-[Bis(4‑methoxy-3,5‑dimethylphenyl)phosphino] P ‑ ferrocenyl}-ethyldi(3,5‑xylyl)phosphine, ≥97.0% (CHN) (R)-1-{(SP)-2-[Di(2 furyl)phosphino]ferrocenyl}ethylbis (2‑methylphenyl)phosphine, ≥97.0% (CHN)

H3C CH3 CH3 (2R)-1-[(1R)-1-[Bis(2-methylphenyl)phosphino] OCH3 ethyl]-2-(di-2-furanylphosphino)ferrocene (acc H H3C H3C P to CAS); Josiphos SL-J452-1 CH3 CH H Fe P 3 ‑ ‑ P CH [849924 73 8] H3C 3 O P Fe C34H32FeO2P2 CH CH3 3 OCH3 FW 590.41 O CH3 88751-100MG 100 mg (2S)-1-[(1S)-1-[Bis(3,5‑dimethylphenyl)phosphino]ethyl]-2-[bis 88751-500MG 500 mg (4‑methoxy-3,5‑dimethylphenyl)phosphino]ferrocene (acc to CAS); Josiphos SL-J418‑2 88751-1G 1g [849924‑48‑7] 88751-5G 5g C46H52FeO2P2 FW 754.70 (S)-1-{(RP)-2-[Di(2‑furyl)phosphino]ferrocenyl}ethylbis 88748-100MG 100 mg (2‑methylphenyl)phosphine, ≥97.0% (CHN) 88748-500MG 500 mg (2S)-1-[(1S)-1-[Bis(2-methylphenyl)phosphino] 88748-1G 1g ethyl]-2-(di-2-furanylphosphino)ferrocene (acc CH3 88748-5G 5g to CAS); Josiphos SL-J452-2 CH3 H [849924‑74‑9] P Fe P O C34H32FeO2P2 (R)-1-{(SP)-2-[Bis(4‑methoxy-3,5‑dimethylphenyl)phosphino] H3C ferrocenyl}-ethylbis(2‑methylphenyl)phosphine FW 590.41 O

88752-100MG 100 mg CH3 H3CO H C 88752-500MG 500 mg 3 CH3 H P 88752-1G 1g H C 3 P Fe H C 88752-5G 5g 3 CH3

H3CO (R)-1-[(SP)-2-(Di-tert-butylphosphino)ferrocenyl]ethyl- CH3 diphenylphosphine, ≥97.0% (CHN) (1R)-1-[Bis(4‑methoxy-3,5‑dimethylphenyl)phosphino]-2-[(1R)-1-[bis (1R)-1-[Bis(1,1-dimethylethyl)phosphino]-2- (2‑methylphenyl)phosphino]ethyl]ferrocene (acc to CAS); Josiphos SL- [(1R)-1-(diphenylphosphino)ethyl]ferrocene J425‑1 CH (acc to CAS); Josiphos SL-J502-1 H C 3 H [849924‑49‑8] ‑ ‑ 3 P [223120 71 6] H3C P Fe C44H48FeO2P2 C32H40FeP2 H3C CH3 FW 726.64 FW 542.45 H3C CH3 ≥97.0% (CHN) 88749-100MG 100 mg 88753-100MG 100 mg 88749-500MG 500 mg 88753-500MG 500 mg 88749-1G 1g 88753-1G 1g 88749-5G 5g 88753-5G 5g

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(1) Sturm, T. et al. Chimia , 55, 688. (2) Sturm, T. et al. Adv. Synth. Catal. (S)-1-[(RP)-2-(Di-tert-butylphosphino)ferrocenyl]ethyl- References: 2001 diphenylphosphine, ≥97.0% (CHN) 2003, 345, 160. (3) Solvias AG, unpublished screening results. (4)(a) Morgan, J. B.; Morken, J. P. J. Am. Chem. Soc. 2004, 126, 15338. (b) Moran, W. J.; Morken, J. P. Org. Lett. 2006, 6, (1S)-1-[Bis(1,1-dimethylethyl)phosphino]-2- 2413. (5) Tanaka, K. et al. Angew. Chem., Int. Ed. 2005, 44, 7260. (6) Kong, J-R. et al. J. [(1S)-1-(diphenylphosphino)ethyl]ferrocene Am. Chem. Soc. 2006, 128, 718. (7) Houpis, I. N. et al. Org. Lett. 2005, 7, 1947. CH3 (acc to CAS); Josiphos SL-J502-2 H P CH3 ‑ ‑ F CCF F C CF [223121 01 5] Fe P CH3 3 3 3 3 CF F C C32H40FeP2 H3C CH 3 3 3 W001-1 P W001-2 P FW 542.45 H C CH P P 3 3 65671 65672 Fe Fe CH3 CF3 F3C H3C 88754-100MG 100 mg 88754-500MG 500 mg 88754-1G 1g W002-1 P W002-2 P P 88754-5G 5g 65673 65674 P Fe CH3 Fe H3C

Ligand Portfolio (R)-1-[(SP)-2-(Di-tert-butylphosphino)ferrocenyl]ethylbis ® (2‑methylphenyl)phosphine, ≥97.0% (CHN) W003-1 P W003-2 P (1R)-1-[Bis(1,1-dimethylethyl)phosphino]-2- P 65675 65676 P [(1R)-1-[bis(2-methylphenyl)phosphino]ethyl] Fe Fe H C CH3 H C CH 3 CH3 3 ferrocene (acc to CAS); Josiphos SL-J505-1 3 H Solvias H C ‑ ‑ 3 P [849924 76 1] H3C P Fe OCH H3C 3 H3CO CH3 C34H44FeP2 H C CH3 F3C CF3 F3C CF 3 H3C 3 CH3 H C CH3 CF H C FW 570.51 3 CH3 H CO 3 F3C 3 W005-1 3 W005-2 OCH3 P P P P 65677 H3C 65678 CH3 Fe Fe CH CF 88755-100MG 100 mg 3 3 F3C H3C 88755-500MG 500 mg F C CF3 F3C CF 88755-1G 1g 3 3 CF3 F3C 88755-5G 5g W008-1 W008-2 P P P P 65681 65682 Fe Fe CH3 CF3 F3C H3C (S)-1-[(RP)-2-(Di-tert-butylphosphino)ferrocenyl]ethylbis (2‑methylphenyl)phosphine, ≥97.0% (CHN) CH3 CH3 H3C CH H3C CH 3 CH3 3 CH3 (1S)-1-[Bis(1,1-dimethylethyl)phosphino]-2- H C H3C H3C W009-1 3 W009-2 H3C [(1S)-1-[bis(2-methylphenyl)phosphino]ethyl] P P P P CH CH CH CH3 CH3 65683 3 65684 3 3 Fe Fe ferrocene (acc to CAS); Josiphos SL-J505-2 H CH H3C H3C H3C H3C ‑ ‑ P 3 [849924 77 2] Fe P CH3 H C C34H44FeP2 3 CH3 FW 570.51 H C CH3 3 O O O CO2H 88756-100MG 100 mg OH OEt 88756-500MG 500 mg O BnO

88756-1G 1g Rh / Walphos W001, 95% ee Rh / W001, 92% ee -1 88756-5G 5g TON 5000; TOF ~800 h-1 TON ~300, TOF ~20 h medium scale production feasibility study Novartis / Solvias [2] Lilly [7] Walphos Like Josiphos, Walphos ligands are modular but form 8‑membered Rh / W001 or W008 O O + H O O metallocycles due to the additional phenyl ring attached to the B 2 B [4] 1 s/c 50, 15-35 bar cyclopentadiene ring. There are noticeable electronic effects but the R R scope of this ligand family is still under investigation; several derivatives 60-90% 85 - >95% ee are available from Solvias on a research scale. Walphos ligands show O O promise for various enantioselective hydrogenations and pertinent H Rh / W002 examples are depicted in Figure 1. Rh/Walphos catalysts gave good + s/c 10-20 [5] 1–3 CONMe2 CONMe results for dehydro amino and itaconic acid derivatives (ee 92–95%, CH Cl , 80 °C 2 R 2 2 preferred ligands W001, W002, W004, W006 and W009) and of vinyl R H 4 R = (subst)Ar, Alk boronates (see Figure 1). Ru/Walphos complexes were highly selective 50-90% for β-keto esters (ee 91‑95%, W001, W002, W003 and W005) and 97 - >99% ee 2,3 R acetyl acetone (ee >99.5%, s/c 1000, W001). Recently, two novel O Rh / W009 COOMe [6] + + H2 transformations were reported to be catalyzed by Rh/Walphos complexes s/c 50 R COOMe OH with high enantioselectivities (Figure 1): the 4+2‑addition of 4‑alkynals 1 bar, 80 °C R = (subst)Alk with an acryl amide by Tanaka and co-workers5 and the reductive 80 - 97% 88 - 93% ee coupling of enynes with α-keto esters by Krische's group.6 The first industrial application has just been realized in collaboration with Figure 1 Speedel/Novartis for the hydrogenation of SPP100‑SyA, a sterically demanding α,β-unsaturated acid intermediate of the renin inhibitor SPP100.2 The process has already been operated on a multiton scale. Lilly's chemists7 developed a process of a PPAR agonist using the Rh-catalyzed asymmetric hydrogenation of (Z)-cinnamic acid as key step. A screen of over 250 catalysts and conditions revealed Rh-W001 as the most effective ligand, giving the product in 92% ee.

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(R)-1-{(RP)-2-[2-(Diphenylphosphino)phenyl]ferrocenyl}ethyl- (R)-1-{(RP)-2-[2-(Diphenylphosphino)phenyl]ferrocenyl}ethylbis[3,5‑bis-(trifluoromethyl)phenyl]phosphine, ≥97.0% (19F- dicyclohexylphosphine, ≥97.0% (CHN) NMR) (1S)-1-[(1R)-1-(Dicyclohexylphosphino)ethyl]-

F3C CF3 2-[2-(diphenylphosphino)phenyl]ferrocene P (acc to CAS); Walphos SL-W003-1 H

P Solvias P ‑ ‑ H [388079 60 5] Fe P CF3 CH C42H48FeP2 3 Fe CH3 FW 670.62

CF3 65675-100MG 100 mg ® ‑ 65675-500MG 500 mg (1S)-1-[(1R)-1-[Bis[3,5 bis(trifluoromethyl)phenyl]phosphino]ethyl]-2-[2- Portfolio Ligand (diphenylphosphino)phenyl]ferrocene (acc to CAS); Walphos SL-W001‑1 65675-1G 1g [387868‑06‑6] 65675-5G 5g C46H32F12FeP2 FW 930.52 (S)-1-{(SP)-2-[2-(Diphenylphosphino)phenyl]ferrocenyl}ethyl- 65671-100MG 100 mg dicyclohexylphosphine, ≥97.0% (CHN) 65671-500MG 500 mg (1R)-1-[(1S)-1-(Dicyclohexylphosphino)ethyl]- 65671-1G 1g 2-[2-(diphenylphosphino)phenyl]ferrocene P 65671-5G 5g H (acc to CAS); Walphos SL-W003-2 P [849925‑19‑5] Fe H3C (S)-1-{(SP)-2-[2-(Diphenylphosphino)phenyl]ferrocenyl}ethyl- C42H48FeP2 bis[3,5‑bis-(trifluoromethyl)phenyl]phosphine, ≥97.0% (19F- FW 670.62 NMR) 65676-100MG 100 mg 65676-500MG 500 mg F3C CF3 65676-1G 1g P H 65676-5G 5g F3C P Fe H C 3 (R)-1-{(RP)-2-[2-[Bis(4‑methoxy-3,5‑dimethylphenyl)phos- CF3 phino]phenyl]ferrocenyl}ethylbis[3,5‑bis(trifluoromethyl) phenyl]phosphine, ≥95.0% (1R)-1-[(1S)-1-[Bis(3,5‑bis(trifluoromethyl)phenyl)phosphino]ethyl]-2-[2- ‑ (diphenylphosphino)phenyl]ferrocene (acc to CAS); Walphos SL-W001 2 CH3 CH3 [849925‑17‑3] H3CO OCH3 F3C CF3 C46H32F12FeP2 FW 930.52 H3C P CH3 H 65672-100MG 100 mg P CF3 Fe 65672-500MG 500 mg CH3

65672-1G 1g CF3 65672-5G 5g (1S)-1-[(1R)-1-[Bis[3,5‑bis(trifluoromethyl)phenyl]phosphino]ethyl]-2-[2- [bis(4‑methoxy-3,5‑dimethylphenyl)phosphino]phenyl]ferrocene (acc to (R)-1-{(RP)-2-[2-(Diphenylphosphino)phenyl]ferrocenyl}ethyl- ‑ ≥ CAS); Walphos SL-W005 1 diphenylphosphine, 97.0% (CHN) [494227‑30‑4] (1S)-1-[(1R)-1-(Diphenylphosphino)ethyl]-2- C52H44F12FeO2P2 [2-(diphenylphosphino)phenyl]ferrocene (acc FW 1046.68 P H 65677-100MG 100 mg to CAS); Walphos SL-W002-1 P [388079‑58‑1] Fe 65677-500MG 500 mg CH C42H36FeP2 3 65677-1G 1g FW 658.53 65677-5G 5g 65673-100MG 100 mg 65673-500MG 500 mg (S)-1-{(SP)-2-[2-[Bis(4‑methoxy-3,5‑dimethylphenyl)phos- 65673-1G 1g phino]phenyl]ferrocenyl}ethylbis[3,5‑bis(trifluoromethyl) 65673-5G 5g phenyl]phosphine, ≥97.0%

CH3 CH3 (S)-1-{(SP)-2-[2-(Diphenylphosphino)phenyl]ferrocenyl}ethyl- H3CO OCH3 diphenylphosphine, ≥97.0% (CHN) F3C CF3 H3C P CH3 (1R)-1-[(1S)-1-(Diphenylphosphino)ethyl]-2- H F3C P [2-(diphenylphosphino)phenyl]ferrocene (acc Fe P to CAS); Walphos SL-W002-2 H H3C ‑ ‑ P [565184 37 4] Fe CF3 C42H36FeP2 H3C FW 658.53 (1R)-1-[(1S)-1-[Bis[3,5‑bis(trifluoromethyl)phenyl]phosphino]ethyl]-2-[2- [bis(4‑methoxy-3,5‑dimethylphenyl)phosphino]phenyl]ferrocene (acc to 65674-100MG 100 mg CAS); Walphos SL-W005‑2 65674-500MG 500 mg [849925‑20‑8] 65674-1G 1g C52H44F12FeO2P2 65674-5G 5g FW 1046.68 65678-100MG 100 mg 65678-500MG 500 mg 65678-1G 1g 65678-5G 5g

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(R)-1-{(RP)-2-[2-(Diphenylphosphino)phenyl]ferrocenyl}ethyl- (S)-1-{(SP)-2-[2-(Dicyclohexylphosphino)phenyl]ferrocenyl} di(3,5‑xylyl)phosphine, ≥97.0% (CHN) ethylbis[3,5‑bis(trifluoromethyl)phenyl]phosphine, ≥97.0% (NMR) H3C CH3

F3C CF3 P H P CH 3 P Fe H F3C P CH3 Fe CH 3 H3C CF (1S)-1-[(1R)-1-[Bis(3,5‑dimethylphenyl)phosphino]ethyl]-2-[2-(diphenyl- 3 phosphino)phenyl]ferrocene (acc to CAS); Walphos SL-W006‑1 (1R)-1-[(1S)-1-[bis[3,5‑bis(trifluoromethyl)phenyl]phosphino]ethyl]-2-[2- [494227‑31‑5] (dicyclohexylphosphino)phenyl]ferrocene (acc to CAS); Walphos SL- C46H44FeP2 W008‑2 FW 714.63 [849925‑22‑0] 65679-100MG 100 mg C46H44F12FeP2 Ligand Portfolio 65679-500MG 500 mg FW 942.61 ® 65679-1G 1g 65682-100MG 100 mg 65679-5G 5g 65682-500MG 500 mg 65682-1G 1g

(S)-1-{(SP)-2-[2-(Diphenylphosphino)phenyl]ferrocenyl}ethyl- 65682-5G 5g Solvias di(3,5‑xylyl)phosphine, ≥97.0% (CHN) (R)-1-{(R )-2-[2-[Di(3,5‑xylyl)phosphino]phenyl]ferrocenyl} H C CH P 3 3 ethyldi(3,5‑xylyl)phosphine, ≥97.0% (CHN) P H CH3 CH3 H3C P Fe H3C CH3 H3C H3C P CH3 CH3 H P CH3 (1R)-1-[(1S)-1-[Bis(3,5‑dimethylphenyl)phosphino]ethyl]-2-[2-(diphenyl- Fe phosphino)phenyl]ferrocene (acc to CAS); Walphos SL-W006‑2 CH3 [849925‑21‑9] CH3 C46H44FeP2 ‑ FW 714.63 (1S)-1-[(1R)-1-[Bis(3,5 dimethylphenyl)phosphino]ethyl]-2-[2-[bis (3,5‑dimethylphenyl)phosphino]phenyl]ferrocene (acc to CAS); Walphos 65680-100MG 100 mg SL-W009‑1 65680-500MG 500 mg [494227‑33‑7] 65680-1G 1g C50H52FeP2 65680-5G 5g FW 770.74 65683-100MG 100 mg

(R)-1-{(RP)-2-[2-(Dicyclohexylphosphino)phenyl]ferrocenyl} 65683-500MG 500 mg ethylbis[3,5‑bis(trifluoromethyl)phenyl]phosphine, ≥97.0% 65683-1G 1g (NMR) 65683-5G 5g

F3C CF3 (S)-1-{(SP)-2-[2-[Di(3,5‑xylyl)phosphino]phenyl]ferrocenyl} P H ethyldi(3,5‑xylyl)phosphine, ≥97.0% (CHN) P CF3 Fe CH3 CH3 CH3

CF3 H3C CH3 ‑ H3C P CH3 (1S)-1-[(1R)-1-[bis[3,5 bis(trifluoromethyl)phenyl]phosphino]ethyl]-2-[2- H (dicyclohexylphosphino)phenyl]ferrocene (acc to CAS); Walphos SL- H3C P Fe W008‑1 H3C ‑ ‑ [494227 32 6] CH3 C46H44F12FeP2 FW 942.61 (1R)-1-[(1S)-1-[Bis(3,5‑dimethylphenyl)phosphino]ethyl]-2-[2-[bis 65681-100MG 100 mg (3,5‑dimethylphenyl)phosphino]phenyl]ferrocene (acc to CAS); Walphos ‑ 65681-500MG 500 mg SL-W009 2 [849925‑24‑2] 65681-1G 1g C50H52FeP2 65681-5G 5g FW 770.74 65684-100MG 100 mg 65684-500MG 500 mg 65684-1G 1g 65684-5G 5g

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(1)(a) Ireland, T. et al. Angew. Chem., Int. Ed. Engl. , 38, 3212. (b) Ireland, (R)-1-{(RP)-2-[2-(Diphenylphosphino)phenyl]ferrocenyl}ethyl- References: 1999 di(2‑norbornyl)phosphine, ≥97.0% (CHN) T. et al. Chem.- Eur. J. 2002, 8, 843. (c) Lotz, M. et al. Angew. Chem., Int. Ed. 2002, 41, 4708. (d) Tappe, K.; Knochel, P. Tetrahedron: Asymmetry 2004, 15, 91. (2) Spindler, F. et al. Tetrahedron: Asymmetry 2004, 15, 2299. (3) Lautens, M. et al. Org. Lett. 2002, 4, 3465. (4)(a) Chuzel, O. et al. Org. Lett. 2006, 8, 5943. (b) Deschamp, J. et al. Angew. Chem., Int. Ed. 2006, 45, 1292. P H Solvias P Fe CH3 T001-1 P T001-2 P H H (1S)-1-[(1R)-1-[Bis(bicyclo[2.2.1]hept-2‑yl)phosphino]ethyl]-2-[2- ® 73475 Fe P 73476 P Fe H3C CH3 (diphenylphosphino)phenyl]ferrocene (acc to CAS); Walphos SL-W022‑1 N N Portfolio Ligand H C CH [849925‑29‑7] 3 3 C44H48FeP2 FW 694.64

100 mg P 65685-100MG T002-1 T002-2 P 65685-500MG 500 mg H H 07541 Fe 07542 P P Fe H C 65685-1G 1g 3 N N CH3 H C 3 CH3 65685-5G 5g

(S)-1-{(SP)-2-[2-(Diphenylphosphino)phenyl]ferrocenyl}ethyl- NBoc di(2‑norbornyl)phosphine, ≥97.0% (CHN) Rh / T001 [3] R N + R2NH 2 NHBoc 75-90% 84-96% ee P H P Fe O HO HO + Cu / Taniaphos [4] H3C COOMe + PhSiH COOMe+ COOMe R 3 R R -40 °C threo ‑ erythro (1R)-1-[(1S)-1-[Bis(bicyclo[2.2.1]hept-2 yl)phosphino]ethyl]-2-[2- 70-99% (diphenylphosphino)phenyl]ferrocene (acc to CAS); Walphos SL-W022‑2 R = Alk, (subst) Ph ‑ ‑ R' = H, preferred ligand T001, 50-88% erythro, ee 68-97 [849925 45 7] R' = Me, preferred ligand T002, 86-95% erythro, ee 83-95% C44H48FeP2 FW 694.64 Figure 1 65686-100MG 100 mg 65686-500MG 500 mg

65686-1G 1g (RP)-1‑Dicyclohexylphosphino-2-[(R)-α-(dimethylamino)-2- 65686-5G 5g (dicyclohexylphosphino)benzyl]ferrocene, ≥97.0% (CHN) (1S)-1-(Dicyclohexylphosphino)-2-[(R)-[2-(dicyclo- Taniaphos hexylphosphino)phenyl](dimethylamino)methyl] Compared to Josiphos, the Taniaphos ligands developed by the Knochel ferrocene (acc to CAS); Taniaphos SL-T002-1 P C H FeNP group1 have an additional phenyl ring inserted at the side chain of the 43 63 2 H FW 711.76 Fe Ugi amine. Besides the two-phosphine moieties, the substituent at the P H3C N stereogenic center can also be varied and, up to now, three generations H3C of Taniaphos ligands with different substituents at the α-position have been prepared. Several Taniaphos ligands are being marketed by Solvias in collaboration with Umicore and selected derivatives are being 07541-100MG 100 mg produced on a multikilogram scale. 07541-500MG 500 mg 07541-1G 1g A variety of Taniaphos ligands are very selective in a number of model hydrogenation reactions.1,2 Both the nature of two phosphine moieties, 07541-5G 5g as well as the substituent and the configuration of the stereogenic center at the α-position, have strong effects on the catalytic performance, (SP)-1‑Dicyclohexylphosphino-2-[(S)-α-(dimethylamino)-2- sometimes even on the sense of induction. Taniaphos complexes are (dicyclohexylphosphino)benzyl]ferrocene, ≥97.0% (CHN) highly active and stereoselective for the Rh catalyzed hydrogenation of (1R)-1-(Dicyclohexylphosphino)-2-[(S)-[2-(dicyclo- methyl acetamido cinnamate (ee 94–99.5%) and dimethyl itaconate (91–99.5% ee), and in the Ru catalyzed hydrogenation of β-ketoesters hexylphosphino)phenyl](dimethylamino)methyl] (94–98% ee), cyclic β-ketoesters (85–94% ee, 99% de of anti-product, ferrocene (acc to CAS); Taniaphos SL-T002-2 P s/c up to 25,000) and 1,3‑diketones (97–99.4% ee, ~99% de of anti- C43H63FeNP2 H – FW 711.76 P Fe product). Enamides are hydrogenated with 92 97% ee's but low TOFs CH β N 3 (Rh/T021) and a -dehydroacetamido acid with 99.5% (Rh/T003). CH3 Recently, a variety of highly enantioselective transformations were 3,4 described using Taniaphos complexes. Selected reactions are depicted 07542-100MG 100 mg in Figure 1. T001 was found to be very selective for the Rh catalyzed 07542-500MG 500 mg nucleophilic ring opening of an azabicycle.3 Cu Taniaphos complexes were also very effective for the reductive addition of aldehydes4a to 07542-1G 1g methyl acrylate and of methyl ketones to methyl acrylate.4b 07542-5G 5g

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R COOMe [Rh(nbd) ]BF / M004; 5 bar, rt (RP)-1-[(R)-α-(Dimethylamino)-2-(diphenylphosphino)ben- 2 4 zyl]-2‑diphenylphosphinoferrocene, ≥97.0% (CHN) O NHCbz [4] R = H, Me, Et, OSiR3, CF3 ee 80-97%, yield 80-97% (2S)-1-[(R)-(Dimethylamino)[2-(diphenylphos- Boc R N phino)phenyl]methyl]-2-(diphenylphosphino) R ferrocene (acc to CAS); Taniaphos SL-T001-1 P Rh / M001 [5] + R2NH C43H39FeNP2 H R2N BocHN R FW 687.57 Fe P R H C 3 N R = H, Me 80 - >95% H3C R' = H, Me, MeO, F 94 - >99% ee

Figure 1 73475-100MG 100 mg 73475-500MG 500 mg 73475-1G 1g (SP,S′P)-1,1′-Bis[(R)-α-(dimethylamino)benzyl]-2,2′-bis 73475-5G 5g (diphenylphosphino)ferrocene, ≥97.0% (CHN) Ligand Portfolio (2R,2′R)-1,1′-Bis[(R)-(dimethylamino)phenyl- ® (SP)-1-[(S)-α-(Dimethylamino)-2-(diphenylphosphino)benzyl]- ′ H3C CH3 2‑diphenylphosphinoferrocene, ≥97.0% (CHN) methyl]-2,2 -bis(diphenylphosphino)ferrocene (acc to CAS); Mandyphos SL-M001-1 N P (2R)-1-[(S)-(Dimethylamino)[2-(diphenylphos- C H FeN P 52 50 2 2 Fe H phino)phenyl]methyl]-2-(diphenylphosphino) FW 820.76 H

Solvias ferrocene (acc to CAS); Taniaphos SL-T001-2 P H3C C43H39FeNP2 H N P FW 687.57 P Fe H3C N CH3 CH3

73463-100MG 100 mg 73476-100MG 100 mg 73463-500MG 500 mg 73476-500MG 500 mg 73463-1G 1g 73476-1G 1g 73463-5G 5g 73476-5G 5g

(RP,R′P)-1,1′-Bis[(S)-α-(dimethylamino)benzyl]-2,2′-bis Mandyphos (Ferriphos) (diphenylphosphino)ferrocene, ≥97.0% (CHN) Ferriphos was first prepared by Ito and coworkers1 as a bidentate analog (2S,2′S)-1,1′-Bis[(S)-(dimethylamino)phenyl- 2 of PPFA. In 1998, Knochel developed a general synthesis for a highly methyl]-2,2′-bis(diphenylphosphino)ferrocene H3C CH3 modular ligand family which was later called Mandyphos in which not (acc to CAS); Mandyphos SL-M001-2 N only the PR' moieties but also the substituents at the side chain can be ‑ ‑ P 2 [223725 09 5] Fe H used for fine tuning purposes. Selected Mandyphos derivatives are C52H50FeN2P2 H commercialized by Solvias in collaboration with Umicore. Even though FW 820.76 CH the scope of this family is not yet fully explored, screening results3 P N 3 indicate high enantioselectivities as well as high activity for several CH3 Mandyphos derivatives in the Rh catalyzed hydrogenation of dehydroamino acid derivatives (preferred ligand M004,95– >99% ee, s/c up to 20,000) and the Ru catalyzed hydrogenation of tiglic acid 73464-100MG 100 mg (M004, 97% ee). M004 was also the ligand of choice for the Rh 73464-500MG 500 mg 4 catalyzed hydrogenation of various methyl 2‑furyl acrylates while 73464-1G 1g Rh/Ferriphos was highly selective for Rh catalyzed ring opening of 73464-5G 5g azabicycles with amines5 (see Figure 1). Several Mandyphos derivatives are being produced on a multikilogram scale. (SP,S′P)-1,1′-Bis(dicyclohexylphosphino)-2,2′-bis[(R)-α- (dimethylamino)benzyl]ferrocene, ≥97.0% (CHN) References: (1) Sawamura, M. et al. Tetrahedron: Asymmetry 1991, 2, 593. (2)(a) Almena Perea, J. et al. Tetrahedron Lett. 1998, 39, 8073. (b) Lotz, M. et al. Tetrahedron: Asymmetry (1R,1′R′)-1,1′-Bis(dicyclohexylphosphino)-2,2′- 1999, 10, 1839. (c) Almena Perea, J. et al. Tetrahedron: Asymmetry 1999, 10, 375. bis[(R)-(dimethylamino)phenylmethyl]ferrocene H3C CH3 (3) Spindler, F. et al. Tetrahedron: Asymmetry 2004, 15, 2299. (4) Hashmi, A. S. K. et al. N Chem. -Eur. J. 2006, 12, 5376. (5) Cho, Y-h. et al. J. Am. Chem. Soc. 2006, 128, 6837. (acc to CAS); Mandyphos SL-M002-1 ‑ ‑ P [494227 35 9] Fe H C52H74FeN2P2 H

H3C CH3 FW 844.95 H3C N CH H C N N P P 3 3 P H3C M001-1 Fe M001-2 Fe 73463 73464 N P P N H C CH 3 CH3 H3C 3 73465-100MG 100 mg 73465-500MG 500 mg 73465-1G 1g OCH3 OCH3 H3C CH3 H3C CH3 73465-5G 5g

H3C CH H3C CH3 3

N CH3 H3C N H3CO P P OCH3 Fe Fe M004-1 H3C M004-2 CH3

73469 CH3 73470 H3C N P P N H3C CH CH3 H3C 3 OCH3 H3CO

CH3 H3C H3C CH3 H3C CH3 OCH3 OCH3

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(RP,R′P)-1,1′-Bis(dicyclohexylphosphino)-2,2′-bis[(S)-α- (SP,S′P)-1,1′-Bis[bis(4‑methoxy-3,5‑dimethylphenyl)phos- (dimethylamino)benzyl]ferrocene, ≥97.0% (CHN) phino]-2,2′-bis[(R)-α-(dimethylamino)benzyl]ferrocene, ≥97.0% (CHN) (1S,1′S)-1,1′-Bis(dicyclohexylphosphino)-2,2′- H3C CH3 bis[(S)-(dimethylamino)phenylmethyl]ferrocene OCH N 3 (acc to CAS); Mandyphos SL-M002-2 H3C CH3

P Solvias CH [849924‑78‑3] Fe H3C H3C 3 H N C52H74FeN2P2 H FW 844.95 H3CO P P CH3 Fe N H C H 3 H CH3 ®

H3C N P CH3 Portfolio Ligand H3C H C 73466-100MG 100 mg 3 OCH3 73466-500MG 500 mg CH3 H3CO CH3 73466-1G 1g ′ ′ ‑ ‑ ′ 73466-5G 5g (1R,1 R)- 1,1 -Bis[bis(4 methoxy-3,5 dimethylphenyl)phosphino]-2,2 -bis [(R)-(dimethylamino)phenylmethyl]ferrocene (acc to CAS); Mandyphos ‑ ′ ′ ‑ SL-M004 1 (SP,S P)-1,1 -Bis{bis[3,5 bis(trifluoromethyl)phenyl]phos- ‑ ‑ ′ α [494227 37 1] phino}-2,2 -bis[(R)- -(dimethylamino)benzyl]ferrocene, C H FeN O P ≥ 19 64 74 2 4 2 97.0% ( F-NMR) FW 1053.08

F3C CF3 73469-100MG 100 mg

F3C H3C CH3 73469-500MG 500 mg N 73469-1G 1g P Fe 73469-5G 5g F C H 3 H

H3C ′ ′ ‑ ‑ N P CF3 (RP,R P)-1,1 -Bis[bis(4 methoxy-3,5 dimethylphenyl)phos- H3C phino]-2,2′-bis[(S)-α-(dimethylamino)benzyl]ferrocene, F3C ≥97.0% (CHN) CF3 CF3 OCH3 (1R,1′R)-1,1′-Bis[bis[3,5‑bis(trifluoromethyl)phenyl]phosphino]-2,2′-bis H3C CH3 H C CH [(R)-(dimethylamino)phenylmethyl]ferrocene (acc to CAS); Mandyphos 3 3 CH3 ‑ N SL-M003 1 P OCH3 [494227‑36‑0] Fe H CH3 C60H42F24FeN2P2 H FW 1364.74 CH3 H3C P N 73467-100MG 100 mg CH3 CH 73467-500MG 500 mg H3CO 3 CH3 73467-1G 1g H3C OCH3 73467-5G 5g (1S,1′S)- 1,1′-Bis[bis(4‑methoxy-3,5‑dimethylphenyl)phosphino]-2,2′-bis [(S)-(dimethylamino)phenylmethyl]ferrocene (acc to CAS); Mandyphos ′ ′ ‑ (RP,R P)-1,1 -Bis{bis[3,5 bis(trifluoromethyl)phenyl]phos- SL-M004‑2 ′ α phino}-2,2 -bis[(S)- -(dimethylamino)benzyl]ferrocene, [849925‑12‑8] ≥ 19 97.0% ( F-NMR) C64H74FeN2O4P2 FW 1053.08 F3C CF3 73470-100MG 100 mg H3C CH3 CF3 N 73470-500MG 500 mg P 73470-1G 1g Fe H CF H 3 73470-5G 5g

CH3 F3C P N CH3 CF3

CF3 F3C

(1S,1′S)-1,1′-Bis[bis[3,5‑bis(trifluoromethyl)phenyl]phosphino]-2,2′-bis [(S)-(dimethylamino)phenylmethyl]ferrocene (acc to CAS); Mandyphos SL-M003‑2 [849925‑10‑6] C60H42F24FeN2P2 FW 1364.74 73468-100MG 100 mg 73468-500MG 500 mg 73468-1G 1g 73468-5G 5g

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(SP,S′P)-1,1′-Bis[(R)-α-(dimethylamino)benzyl]-2,2′-bis[di (SP,S′P)-1,1′-Bis[bis(2‑methylphenyl)phosphino]-2,2′-bis[(R)-α- (3,5‑xylyl)phosphino]ferrocene, ≥97.0% (CHN) (dimethylamino)benzyl]ferrocene, ≥97.0% (CHN) ′ ′ H3C CH3 (1R,1 R)-1,1 -Bis[bis(2-methylphenyl) CH H C CH phosphino]-2,2′-bis[(R)-(dimethylamino) H3C H3C 3 H3C 3 3 CH3 N phenylmethyl]ferrocene (acc to CAS); N P Mandyphos SL-M012-1 P Fe Fe H C H ‑ ‑ H 3 H [831226 37 0] H C56H58FeN2P2 CH3 H C H3C 3 CH P N P CH3 FW 876.87 N 3 H C H3C 3 H3C

CH3 CH3 73473-100MG 100 mg (1R,1′R)-1,1′-Bis[bis(3,5‑dimethylphenyl)phosphino]-2,2′-bis[(R)- 73473-500MG 500 mg (dimethylamino)phenylmethyl]ferrocene (acc to CAS); Mandyphos SL- 73473-1G 1g

Ligand Portfolio M009‑1 73473-5G 5g

® [793718‑16‑8] C60H66FeN2P2 FW 932.97 (RP,R′P)-1,1′-Bis[bis(2‑methylphenyl)phosphino]-2,2′-bis[(S)-α- (dimethylamino)benzyl]ferrocene, ≥97.0% (CHN) 73471-100MG 100 mg (1S,1′S)-1,1′-Bis[bis(2-methylphenyl) Solvias 73471-500MG 500 mg ′ H3C CH3 73471-1G 1g phosphino]-2,2 -bis[(S)-(dimethylamino) H C CH3 N 3 73471-5G 5g phenylmethyl]ferrocene (acc to CAS); Mandyphos SL-M012-2 P Fe H [831226‑39‑2] H (RP,R′P)-1,1′-Bis[(S)-α-(dimethylamino)benzyl]-2,2′-bis[di C56H58FeN2P2 H3C ‑ ≥ CH3 (3,5 xylyl)phosphino]ferrocene, 97.0% (CHN) FW 876.87 P H3C N CH3

H3C CH3

H3C CH3 CH3 N 73474-100MG 100 mg P Fe 73474-500MG 500 mg H CH3 H 73474-1G 1g

CH3 H3C P N 73474-5G 5g CH3 CH3

H3C H3C

(1S,1′S)- 1,1′-Bis[bis(3,5‑dimethylphenyl)phosphino]-2,2′-bis[(S)- (dimethylamino)phenylmethyl]ferrocene (acc to CAS); Mandyphos SL- M009‑2 [847997‑73‑3] C60H66FeN2P2 FW 932.97 73472-100MG 100 mg 73472-500MG 500 mg 73472-1G 1g 73472-5G 5g

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Naud Catalyst

Complexes prepared in situ from RuCl2(PPh3)3 and chiral (R)-2-[(RP)-2-(Diphenylphosphino)ferrocenyl]-4‑isopropyl- phosphine-oxazoline ligands (Naud catalysts) are effective catalysts for 2‑oxazoline triphenylphosphine ruthenium(II) chloride the hydrogenation of various aryl ketones with up to 99% ee's and Complex substrate to catalyst ratios of 10,000–50,000. The reaction tolerates high substrate concentrations,1 and several derivatives are being produced on Solvias a multikilogram scale. A pilot process has been developed for the O Ph Ph hydrogenation of 3,5‑bistrifluoromethyl acetophenone.2 The reaction P • P N Fe Ph was carried out twice on a 140 kg scale at 20 bar and 25 °C with H3C

substrate to catalyst ratios of 20,000 with an enantiomeric excess of CH3 ® ‑ • RuCl2 >95%. After crystallization, (R)-3,5 bistrifluoromethyl phenyl ethanol was Portfolio Ligand obtained with an ee between 97.7 and 98.6% in 70% chemical yield ‑ ‑ ‑ (Figure 1). A feasibility study was reported by MSD Sharp & Dome (1S)-1-(Diphenylphosphino)-2-[(R)-4 isopropyl-2 oxazolin-2 yl]ferrocene GmbH for the reduction of a highly functionalized aryl ketone.3 Triphenylphosphine Ruthenium(II) chloride Complex (acc to CAS); Naud Catalyst SK-N003‑1z References: (1) Naud, F. et al. Adv. Synth. Catal. 2006, 348,47‑50. (2) Naud, F. et al. [849921‑25‑1] Org. Process Res. Dev. 2007, 11, 319. (3) Tellers, D. M. et al. Tetrahedron: Asymmetry 2006, C46H43Cl2FeNOP2Ru 17, 550. FW 915.61 ≥97.0% (CHN) 91991-100MG 100 mg

O O • PPh3 91991-500MG 500 mg N003-1 P • PPh3 N003-2 P N Fe Fe N 91991-1G 1g 91991 H3C 91992 CH3 CH3 H3C 91991-5G 5g • RuCl2 • RuCl2

(S)-2-[(SP)-2-(Diphenylphosphino)ferrocenyl]-4‑isopropyl- O OH 2‑oxazoline triphenylphosphine ruthenium(II) dichloride R'' R'' RuCl2(PPh3)3 + N003 Complex, ≥97.0% (CHN) + H2 R' toluene / H2O / NaOH R' (1R)-1-(Diphenylphosphino)-2-[(S)-4-isopropyl- 20-80 bar, r.t. 90 - 99% ee Ph Ph up to 40,000 TON 2-oxazolin-2-yl]ferrocene Triphenylphosphine P O • Ruthenium(II) chloride Complex (acc to CAS); P Ph O F O Naud Catalyst SK-N003-2z Fe N F3C CH ‑ ‑ 3 [212133 11 4] H3C O C46H43Cl2FeNOP2Ru • RuCl2 CF3 FW 915.61 NHCbz 91992-100MG 100 mg RuCl2(PPh3)3 / N003-1 RuCl2(PPh3)3 / N003-2 25°C, 20 bar 40°C, 20 bar 91992-500MG 500 mg 95% ee; TON 20,000;TOF 2000 h-1 -1 93% ee; TON 130; TOF ~8 h 91992-1G 1g pilot process, Solvias/Rohner [2] Feasibility study, MSD Sharp & Dome GmbH [3] 91992-5G 5g Figure 1

Butiphane In many respects the catalytic profile of the Butiphane ligands1 P005‑1 (S,S,S,S)-2,3‑Bis(2,5‑dimethyl-phospholanyl)benzo[b]thio- (53361) and P005‑2 (53362) is rather similar to that of other phene cyclooctadiene rhodium(I) tetrafluoroborate Com- phospholane diphosphines such as DuPhos and its many analogs.2 Up to plex, ≥97.0% (19F-NMR) now, the potential of the ligand has only been demonstrated in the Rh

Methyl-Butiphane SK-P005-2a - catalyzed hydrogenation of dehydroamino acid derivatives, enamides, H C CH3 BF4 1 ‑ ‑ 3 and itaconates, achieving ee values of up to 98.7%. [849920 73 6] P C H BF P RhS 28 40 4 2 + FW 660.34 Rh References: (1) Berens, U. et al. Eur. J. Org. Chem. 2006, 2100. (2) Cobley, C. J.; Moran, P. S P H. In Handbook of Homogeneous Hydrogenation; de Vries, J. G.; Elsevier C. J., Eds.; Wiley- H3C CH3 VCH, 2007; p 773.

(R,R,R,R)-2,3‑Bis(2,5‑dimethyl-phospholanyl)benzo[b]thio- 53362-100MG 100 mg phene cyclooctadiene rhodium(I) tetrafluoroborate Com- 53362-500MG 500 mg plex, ≥97.0% (19F-NMR) 53362-1G 1g Methyl-Butiphane SK-P005-1a 53362-5G 5g CH BF - ‑ ‑ H3C 3 4 [511543 00 3] P C28H40BF4P2RhS Rh+ FW 660.34 S P H3C CH3

53361-100MG 100 mg 53361-500MG 500 mg 53361-1G 1g 53361-5G 5g

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Kit

Solvias® Chiral Ligands Kit phenyl)phosphine (Aldrich 88750) (R)-1-{(SP)-2-[Di(2‑furyl)phosphino]ferrocenyl}ethylbis(2‑methylphenyl)phosphine (Aldrich  Chiral Phosphine Ligands, Kit from Solvias® 88751) ‑ ‑ ≥ (S)-1-{(RP)-2-[Di(2 furyl)phosphino]ferrocenyl}ethylbis(2 methylphenyl)phosphine (Aldrich 97% (each component) 88752) (R)-1-[(SP)-2-(Di-tert-butylphosphino)ferrocenyl]ethyldiphenylphosphine (Aldrich 88753) (S)-1-[(RP)-2-(Di-tert-butylphosphino)ferrocenyl]ethyldiphenylphosphine (Aldrich 88754) (R)-1-[(SP)-2-(Di-tert-butylphosphino)ferrocenyl]ethylbis(2‑methylphenyl)phosphine (Aldrich 88755) (S)-1-[(RP)-2-(Di-tert-butylphosphino)ferrocenyl]ethylbis(2‑methylphenyl)phosphine (Aldrich 88756) (SP,S′P)-1,1′-Bis[(R)-α-(dimethylamino)benzyl]-2,2′-bis(diphenylphosphino)ferrocene (Aldrich 73463) (RP,R′P)-1,1′-Bis[(S)-α-(dimethylamino)benzyl]-2,2′-bis(diphenylphosphino)ferrocene (Aldrich 73464) (SP,S′P)-1,1′-Bis(dicyclohexylphosphino)-2,2′-bis[(R)-α-(dimethylamino)benzyl]ferrocene (Al- Ligand Portfolio drich 73465)

® (RP,R′P)-1,1′-Bis(dicyclohexylphosphino)-2,2′-bis[(S)-α-(dimethylamino)benzyl]ferrocene (Al- drich 73466) (SP,S′P)-1,1′-Bis{bis[3,5‑bis(trifluoromethyl)phenyl]phosphino}-2,2′-bis[(R)-α-(dimethylamino) benzyl]ferrocene (Aldrich 73467) (RP,R′P)-1,1′-Bis{bis[3,5‑bis(trifluoromethyl)phenyl]phosphino}-2,2′-bis[(S)-α-(dimethylamino) benzyl]ferrocene (Aldrich 73468) Solvias ′ ′ ‑ ‑ ′ α Components (SP,S P)-1,1 -Bis[bis(4 methoxy-3,5 dimethylphenyl)phosphino]-2,2 -bis[(R)- -(dimethylami- (R)-2-[(RP)-2-(Diphenylphosphino)ferrocenyl]-4‑isopropyl-2‑oxazoline triphenylphosphine no)benzyl]ferrocene (Aldrich 73469) ′ ′ ‑ ‑ ′ α ruthenium(II) chloride Complex (Aldrich 91991) (RP,R P)-1,1 -Bis[bis(4 methoxy-3,5 dimethylphenyl)phosphino]-2,2 -bis[(S)- -(dimethylami- (S)-2-[(SP)-2-(Diphenylphosphino)ferrocenyl]-4‑isopropyl-2‑oxazoline triphenylphosphine no)benzyl]ferrocene (Aldrich 73470) ′ ′ α ′ ‑ ruthenium(II) dichloride Complex (Aldrich 91992) (SP,S P)-1,1 -Bis[(R)- -(dimethylamino)benzyl]-2,2 -bis[di(3,5 xylyl)phosphino]ferrocene (Al- (R,R,R,R)-2,3‑Bis(2,5‑dimethyl-phospholanyl)benzo[b]thiophene cyclooctadiene rhodium(I) drich 73471) ′ ′ α ′ ‑ tetrafluoroborate Complex (Aldrich 53361) (RP,R P)-1,1 -Bis[(S)- -(dimethylamino)benzyl]-2,2 -bis[di(3,5 xylyl)phosphino]ferrocene (Al- (S,S,S,S)-2,3‑Bis(2,5‑dimethyl-phospholanyl)benzo[b]thiophene cyclooctadiene rhodium(I) drich 73472) ′ ′ ‑ ′ α tetrafluoroborate Complex (Aldrich 53362) (SP,S P)-1,1 -Bis[bis(2 methylphenyl)phosphino]-2,2 -bis[(R)- -(dimethylamino)benzyl]ferro- (R)-1-[(SP)-2-(Diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine (Aldrich 88717) cene (Aldrich 73473) ′ ′ ‑ ′ α (S)-1-[(RP)-2-(Diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine (Aldrich 88718) (RP,R P)-1,1 -Bis[bis(2 methylphenyl)phosphino]-2,2 -bis[(S)- -(dimethylamino)benzyl]ferro- (R)-1-[(SP)-2-(Diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (Aldrich 88719) cene (Aldrich 73474) α ‑ (S)-1-[(RP)-2-(Diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (Aldrich 88720) (RP)-1-[(R)- -(Dimethylamino)-2-(diphenylphosphino)benzyl]-2 diphenylphosphinoferrocene (R)-1-[(SP)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldicyclohexylphosphine (Aldrich 88721) (Aldrich 73475) α ‑ (S)-1-[(RP)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldicyclohexylphosphine (Aldrich 88722) (SP)-1-[(S)- -(Dimethylamino)-2-(diphenylphosphino)benzyl]-2 diphenylphosphinoferrocene (R)-1-[(SP)-2-(Dicyclohexylphosphino)ferrocenylethyl]diphenylphosphine (Aldrich 88723) (Aldrich 73476) ‑ α (S)-1-[(RP)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldiphenylphosphine (Aldrich 88724) (RP)-1 Dicyclohexylphosphino-2-[(R)- -(dimethylamino)-2-(dicyclohexylphosphino)benzyl] (R)-1-[(SP)-2-(Diphenylphosphino)ferrocenyl]ethyldi(3,5‑xylyl)phosphine (Aldrich 88725) ferrocene (Aldrich 07541) ‑ α (S)-1-[(RP)-2-(Diphenylphosphino)ferrocenyl]ethyldi(3,5‑xylyl)phosphine (Aldrich 88726) (SP)-1 Dicyclohexylphosphino-2-[(S)- -(dimethylamino)-2-(dicyclohexylphosphino)benzyl] (R)-1-{(SP)-2-[Bis[3,5‑bis(trifluoromethyl)phenyl]phosphino]ferrocenyl}ethyldicyclohexylphos- ferrocene (Aldrich 07542) ‑ phine (Aldrich 88727) (R)-1-{(RP)-2-[2-(Diphenylphosphino)phenyl]ferrocenyl}ethylbis[3,5 bis-(trifluoromethyl)phe- (S)-1-{(RP)-2-[Bis[3,5‑bis(trifluoromethyl)phenyl]phosphino]-ferrocenyl}ethyldicyclohexyl- nyl]phosphine (Aldrich 65671) ‑ phosphine (Aldrich 88728) (S)-1-{(SP)-2-[2-(Diphenylphosphino)phenyl]ferrocenyl}ethylbis[3,5 bis-(trifluoromethyl)phe- (R)-1-{(SP)-2-[Bis(4‑methoxy-3,5‑dimethylphenyl)phosphino]ferrocenyl}ethyldicyclohexyl- nyl]phosphine (Aldrich 65672) phosphine (Aldrich 88729) (R)-1-{(RP)-2-[2-(Diphenylphosphino)phenyl]ferrocenyl}ethyldiphenylphosphine (Aldrich (S)-1-{(RP)-2-[Bis(4‑methoxy-3,5‑dimethylphenyl)phosphino]ferrocenyl}ethyldicyclohexyl- 65673) phosphine (Aldrich 88730) (S)-1-{(SP)-2-[2-(Diphenylphosphino)phenyl]ferrocenyl}ethyldiphenylphosphine (Aldrich (R)-1-{(SP)-2-[Bis[3,5‑bis(trifluoromethyl)phenyl]phosphino]ferrocenyl}ethyldi(3,5‑xylyl)phos- 65674) phine (Aldrich 88731) (R)-1-{(RP)-2-[2-(Diphenylphosphino)phenyl]ferrocenyl}ethyldicyclohexylphosphine (Aldrich (S)-1-{(RP)-2-[Bis[3,5‑bis(trifluoromethyl)phenyl]phosphino]ferrocenyl}ethyldi(3,5‑xylyl)phos- 65675) phine (Aldrich 88732) (S)-1-{(SP)-2-[2-(Diphenylphosphino)phenyl]ferrocenyl}ethyldicyclohexylphosphine (Aldrich (R)-1-[(SP)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (Aldrich 88733) 65676) ‑ ‑ (S)-1-[(RP)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (Aldrich 88734) (R)-1-{(RP)-2-[2-[Bis(4 methoxy-3,5 dimethylphenyl)phosphino]phenyl]ferrocenyl}ethylbis ‑ (R)-1-{(SP)-2-[Bis[4-(trifluoromethyl)phenyl]phosphino]ferrocenyl}ethyldi-tert-butylphosphine [3,5 bis(trifluoromethyl)phenyl]phosphine (Aldrich 65677) ‑ ‑ (Aldrich 88735) (S)-1-{(SP)-2-[2-[Bis(4 methoxy-3,5 dimethylphenyl)phosphino]phenyl]ferrocenyl}ethylbis ‑ (S)-1-{(RP)-2-[Bis[4-(trifluoromethyl)phenyl]phosphino]ferrocenyl}ethyldi-tert-butylphosphine [3,5 bis(trifluoromethyl)phenyl]phosphine (Aldrich 65678) ‑ (Aldrich 88736) (R)-1-{(RP)-2-[2-(Diphenylphosphino)phenyl]ferrocenyl}ethyldi(3,5 xylyl)phosphine (Aldrich (R)-1-[(SP)-2-[Bis(4‑methoxy-3,5‑dimethylphenyl)phosphino]ferrocenyl}ethyldi-tert-butyl- 65679) ‑ phosphine (Aldrich 88737) (S)-1-{(SP)-2-[2-(Diphenylphosphino)phenyl]ferrocenyl}ethyldi(3,5 xylyl)phosphine (Aldrich (S)-1-[(RP)-2-[Bis(4‑methoxy-3,5‑dimethylphenyl)phosphino]ferrocenyl}ethyldi-tert-butyl- 65680) ‑ phosphine (Aldrich 88738) (R)-1-{(RP)-2-[2-(Dicyclohexylphosphino)phenyl]ferrocenyl}ethylbis[3,5 bis(trifluoromethyl) (R)-1-{(SP)-2-[Di(2‑furyl)phosphino]ferrocenyl}ethyldi(3,5‑xylyl)phosphine (Aldrich 88739) phenyl]phosphine (Aldrich 65681) ‑ (S)-1-{(RP)-2-[Di(2‑furyl)phosphino]ferrocenyl}ethyldi(3,5‑xylyl)phosphine (Aldrich 88740) (S)-1-{(SP)-2-[2-(Dicyclohexylphosphino)phenyl]ferrocenyl}ethylbis[3,5 bis(trifluoromethyl) (R)-1-{(SP)-2-[Di(2‑furyl)phosphino]ferrocenyl}ethyldi-tert-butylphosphine (Aldrich 88741) phenyl]phosphine (Aldrich 65682) ‑ ‑ (S)-1-{(RP)-2-[Di(2‑furyl)phosphino]ferrocenyl}ethyldi-tert-butylphosphine (Aldrich 88742) (R)-1-{(RP)-2-[2-[Di(3,5 xylyl)phosphino]phenyl]ferrocenyl}ethyldi(3,5 xylyl)phosphine (Al- (R)-1-{(SP)-2-[Di(1‑naphthyl)phosphino]ferrocenyl}ethyldi-tert-butylphosphine (Aldrich drich 65683) ‑ ‑ 88743) (S)-1-{(SP)-2-[2-[Di(3,5 xylyl)phosphino]phenyl]ferrocenyl}ethyldi(3,5 xylyl)phosphine (Al- (S)-1-{(RP)-2-[Di(1‑naphthyl)phosphino]ferrocenyl}ethyldi-tert-butylphosphine (Aldrich drich 65684) ‑ 88744) (R)-1-{(RP)-2-[2-(Diphenylphosphino)phenyl]ferrocenyl}ethyldi(2 norbornyl)phosphine (Al- (R)-1-{(SP)-2-[Di(1‑naphthyl)phosphino]ferrocenyl}ethyldi(3,5‑xylyl)phosphine (Aldrich drich 65685) ‑ 88745) (S)-1-{(SP)-2-[2-(Diphenylphosphino)phenyl]ferrocenyl}ethyldi(2 norbornyl)phosphine (Al- (S)-1-{(RP)-2-[Di(1‑naphthyl)phosphino]ferrocenyl}ethyldi(3,5‑xylyl)phosphine (Aldrich drich 65686) 88746) (S)-(-)-(6,6′-Dimethoxybiphenyl-2,2′-diyl)bis(diphenylphosphine) (Aldrich 29511) ′ ′ (R)-1-{(SP)-2-[Bis(4‑methoxy-3,5‑dimethylphenyl)phosphino]ferrocenyl}-ethyldi(3,5‑xylyl) (R)-(+)-(6,6 -Dimethoxybiphenyl-2,2 -diyl)bis(diphenylphosphine) (Aldrich 29510) phosphine (Aldrich 88747) (R)-(6,6′-Dimethoxybiphenyl-2,2′-diyl)bis[bis(3,5‑di-tert-butyl-4‑methoxyphenyl)phosphine] (S)-1-{(RP)-2-[Bis(4‑methoxy-3,5‑dimethylphenyl)phosphino]ferrocenyl}-ethyldi(3,5‑xylyl) (Aldrich 29512) phosphine (Aldrich 88748) (S)-(6,6′-Dimethoxybiphenyl-2,2′-diyl)bis[bis(3,5‑di-tert-butyl-4‑methoxyphenyl)phosphine] (R)-1-{(SP)-2-[Bis(4‑methoxy-3,5‑dimethylphenyl)phosphino]ferrocenyl}-ethylbis(2‑methyl- (Aldrich 29513) phenyl)phosphine (Aldrich 88749) 12000-1KT 1 kit (S)-1-{(RP)-2-[Bis(4‑methoxy-3,5‑dimethylphenyl)phosphino]ferrocenyl}-ethylbis(2‑methyl-

32 sigma-aldrich.com TO ORDER: Contact your local Sigma-Aldrich office (see back cover) or visit sigma-aldrich.com/chemicalsynthesis. UMICORE Precatalysts for Asymmetric Reactions

Sigma-Aldrich® and Umicore have partnered to offer a portfolio of metal precatalysts for rapid screening of asymmetric and cross-coupling reactions. This partnership ensures the reproducibility of milligram-to-ton-scale reactions.

H C H3C 3 O O BARF Ir Cl Rh Ir O Ir Ir O Cl H C H3C 3 693774 683086 683094 683108

H3C O Rh BF BF Cl 4 • x H2O 4 O Rh Rh Rh Rh H3C Cl 683116 683132 683140 683175

H3C H C 3 Cl Cl O CO Rh Rh Cl Rh Ru Cl Cl Rh Rh O CO Cl H3C H3C 683167 683183 686891 683353

I I Cl Cl Ru Ru Ru Ru Cl Cl I Cl Cl Ru Ru Cl I Cl Cl Ru Cl n 683205 683213 683221 683191

H3C CH3 O O Pd Cl O O Pd Pd H3C CH3 Cl Pd(OAc)2 Pd2dba3 683388 683396 683124 683345

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DuPhos and BPE Phospholane Ligands and Complexes

H [((R,R)-Me-BPE)-Rh]+ H In the early 1990s, Burk and coworkers developed new electron-rich C2 (S/C = 500) symmetric bis(phospholane) ligands. The modular nature of these ligands MeOH, 60 psi H , rt, 12 h Ph N(H)Ac allowed for variation of both phosphane substituent and backbone Ph N(H)Ac 2 structures, leading to an extensive library of ligands for enantioselective 95.2% ee catalytic reactions. The large-scale capacity of these robust catalysts is Scheme 1 observed in the efficiency (substrate-to-catalyst (s/c) ratios up to 50,000) and the high activities (TOF >5,000 h-1) in a myriad of enamide and ketone reductions. Under optimized conditions, (R,R)-Me-BPE-Rh reduced N-acetyl α-arylenamides in >95% ee to yield valuable CO2Me 1 N CO Me α-1‑arylethylamines (Scheme 1). CO2Me O N(H)Boc 2 It should be noted that Me-DuPhos-Rh complexes were equally N(H)Ac N(H)CBz effective in asymmetric reductions of prochiral enamides. The general N(H)Boc

DuPhos and BPE utility of these phospholane ligands is illustrated in the incredible diversity-oriented production of a vast array of amino acid derivatives O O 4 CO2Me 2 OMe CO2R AcO OAc (Scheme 2). N R1 N(H)COR3 CO Me 2 R2 AcO OAc Asymmetric Hydrogenation of the C=N Group Burk and co-workers exploited the high activity of the Ethyl-DuPhos ligand via a powerful catalytic reductive amination process.3 The CO2Me CO2Me procedure exhibits general applicability in the reduction of a wide variety C7F15 of N-aroylhydrazones, yielding enantioselectivies for most substrates N(H)Boc F CO2Me N(H)CBz >90% (Scheme 3). Additionally this (Et-DuPhos)-Rh catalyst system N(H)CBz displays exceptionally high chemoselectivies, yielding little or no reduction of unfunctionalized alkenes, alkynes, ketones, aldehydes, and Scheme 2 imines in competition experiments. The synthetic utility of these asymmetric hydrazone reductions is enhanced by their facile reaction at ambient temperature with samarium diiodide, which proceed with no OTf observable loss of optical purity. P P Rh H H Catalytic Hydrogenation of Enamides N p-Me NC H 0.2 mol % N p-Me NC H N 2 6 4 HN 2 6 4 Burk has also pioneered the asymmetric hydrogenation of various O H2 (4 atm), 2-propanol, 2 h, rt O enamido olefins affording highly enantiopure unsaturated amino acid Ph Me Ph Me products.4 The ((S,S)-Et-DuPhos)-Rh) catalyst system controls the 92% ee reactivity of conjugated substrates with high regioselectivies as well. Scheme 3 Under the standard hydrogenation conditions (s/c =500, H2 pressures ranging from 60 to 90 psi, and 0.5−3 h), this catalyst gave less than 2% overreduction, with all products isolated in better than 95% yield.

The authors elaborated upon this outstanding catalyst reactivity by OTf demonstrating a concise and highly selective synthesis of the natural P P product (−)-bulgecinine, preceeded by formation of the key chiral Rh intermediate in 99% yield with 99.3% ee (Scheme 4). OTBS CO Me OTBS H 2 S/C = 500:1 CO2Me H (4 atm), MeOH, 2 h, rt Preparation of Chiral Organics NHAc 2 NHAc 99%, 99.3% ee with C–O Stereogenic Centers Neil Boaz has also utilized rhodium(I)-((R,R)-Me-DuPhos) catalyst 1 to Scheme 4 produce chiral alcohols via the asymmetric hydrogenation of enol esters (Scheme 5). Allylic alcohol derivatives are desirable organic building blocks in diversity-oriented synthesis, because the olefin can be further OAc OAc Rh-(Me-DuPhos) cat. 1 R OAc functionalized after the stereochemistry has been set in the Me Me 5 H2 (30 psi), MeOH, rt H hydrogenation. Under asymmetric hydrogenation conditions, the R R H initially formed propargylic acetate was subsequently reduced to yield the 2a: R = n-C5H11, 98.5% ee Z-allylic acetate. Impressively, the enantioselectivity observed in this 2b: R = Ph, 97.8% ee reaction was very high among the general substrate class 2a-c. 2c: R = CH2CH2OCH2Ph, > 98% ee Burk and co-workers have also designed highly effective catalysts for the asymmetric reduction of C=O bonds under hydrogenation conditions.6 In Scheme 5 this case, the methodology proceeded via use of a chiral Ru(II)Br2-(i-Pr- BPE) complex, which was prepared by reacting [(COD)Ru(2‑methylallyl)2] with the BPE ligand followed by treatment with methanolic HBr. A variety of ketoesters were rapidly hydrogenated as mediated by this catalyst to the hydroxyl esters with very high enantioselectivities >98% ee for the P P Ru alkyl-substituted substrates (Scheme 6). Br Br O OH 0.4 mol % CO2Me CO2Me H2 (60 psi), MeOH/H2O, 18 h 99% ee

Scheme 6

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Enantioselective Hydrogenation P of Alkenes and Imines Au Cl Au Cl The use of gold complexes to effect catalytic transformations is on the P rise, with numerous reports of catalytically active gold species.7 Sanchez H H EtO2C S/C = 1000:1 EtO2C and co-workers have now reported the first example of a gold BPE and DuPhos 8 hydrogenation catalyst utilized in asymmetric transformations. The EtO2C R H2 (4 atm), EtOH, rt EtO2C R authors found that the bulkiest substrate, which incorporates a diethyl 95% ee 2‑naphthylidenesuccinate group, proceeds under the reaction conditions to afford the highest enantioselectivities due to reactant control Scheme 7 (Scheme 7). Future plans in gold-mediated asymmetric hydrogenation involve substantial modifications to the ligand structure to provide higher levels of enantiocontrol in this reaction paradigm. CuF H O (3 mol %) O 2 2 OH O (R,R)-iPr-DuPhos (6 mol %) + B i O La(O Pr)3 (4.5 mol %) Enantioselective Allylboration of Ketones DMF, 1 h, 40 oC (1.2 equiv) The Shibasaki research group has also championed the use of the 99%, 91% ee 9 DuPhos ligand system for asymmetric catalysis. They have now reported Scheme 8 the first general catalytic, enantioselective allylation reaction with ketones, which employs copper salts and a rare-earth lanthanide additive. Impressively, a diverse array of aromatic, heteroaromatic, α,β-unsaturated, and aliphatic ketones are rapidly allylated at ambient Me P temperature and under low catalyst loadings (Scheme 8). The O Me enantioselectivities range from 67 to 92%; however, the reaction Me appears to be quite general for both the allylation and crotylboration P NO reaction paradigms. NO2 Me 2

R CuOTf, Et2Zn R Et2O, -70 °C, 16h Enantioselective Addition of Dialkylzinc NO2 to β-Nitroalkenes NO2 NO2 The use of chiral bis(phosphine) monoxide ligand has found widespread applications in catalysis. Côté et al. reported the use of Me-DuPhos Cl OMe monoxide in the addition of dialkyzinc to nitroalkenes. Various chiral 92% 93% 98% nitroalkanes were synthesized with excellent yields and selectivities 97.5:2.5 93:1 97.5:2.5 (Scheme 9).10 Scheme 9 References: (1) Burk, M. J. et al. J. Am. Chem. Soc. 1996, 118, 5142. (2)(a) Burk, M. J. Acc. Chem. Res. 2000, 33, 363. (b) Burk, M. J. et al. J. Org. Chem. 2003, 68, 5731. (3) Burk, M. J. et al. J. Am. Chem. Soc. 1992, 114, 6266. (4) Burk, M. J. et al. J. Am. Chem. Soc. 1998, 120, 657. (5) Burk, M. J. et al. J. Am. Chem. Soc. 1995, 117, 4423. (6) Burk, M. J. et al. J. Org. Chem. 1999, 64, 3290. (7) Dyker, G. Angew. Chem., Int. Ed. 2000, 39, 4237. (8) Sanchez, F. et al. Chem. Commun. 2005, 3451. (9) Shibasaki, M. et al. J. Am. Chem. Soc. 2004, 126, 8910. (10) Côté, A. et al. Org. Lett. 2007, 9, 85.

(−)-1,2‑Bis[(2R,5R)-2,5‑dimethylphospholano]benzene (−)-1,2‑Bis[(2R,5R)-2,5‑diethylphospholano]benzene (2R,2'R,5R,5'R)-2,2',5,5'-Tetramethyl-1,1'-(o-phenylene) (2R,2'R,5R,5'R)-2,2'-5,5'-Tetraethyl-1,1'-(o-phenylene) H C H3C diphospholane; (R,R)-Methyl-DUPHOS; (R,R)-Me-DUPHOS 3 diphospholane; (R,R)-Ethyl-DUPHOS P CH3 [147253‑67‑6] [136705‑64‑1] P CH C18H28P2 C22H36P2 3 P CH3 FW 306.36 FW 362.47 P H C H3C 3 CH3

S: 22-24/25 Fp: 110 °C (230 °F) 665258-100MG 100 mg 668494-100MG 100 mg 665258-500MG 500 mg 668494-500MG 500 mg 665258-2G 2g 668494-2G 2g (+)-1,2‑Bis[(2S,5S)-2,5‑dimethylphospholano]benzene (+)-1,2‑Bis[(2S,5S)-2,5‑diethylphospholano]benzene (2S,2'S,5S,5'S)-2,2',5,5'-Tetramethyl-1,1'-(o-phenylene) H3C (2S,2'S,5S,5'S)-2,2',5,5'-Tetraethyl-1,1'-(o-phenylene) H3C diphospholane; (S,S)-Methyl-DUPHOS; (S,S)-Me-DUPHOS P CH3 diphospholane; (S,S)-Ethyl-DUPHOS [136735‑95‑0] [136779‑28‑7] P C18H28P2 CH FW 306.36 P CH3 C22H36P2 3 H3C FW 362.47 P H C 3 CH3

665266-100MG 100 mg Fp: 110 °C (230 °F) 665266-500MG 500 mg 665266-2G 2g 668486-100MG 100 mg 668486-500MG 500 mg 668486-2G 2g

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(+)-1,2‑Bis[(2R,5R)-2,5‑diisopropylphospholano]benzene 1,2-Bis[(2S,5S)-2,5-dimethylphospholano]benzene 8 monooxide (R,R)-i-Pr-DUPHOS H3C [136705‑65‑2] S,S-Me-BozPhos; (2S,5S)-1-{2-[(2S,5S)-2,5-Dimethylphos- H3C H3C C26H44P2 CH P 3 pholan-1-yl]phenyl}-2,5-dimethylphospholane 1-oxide P FW 418.58 CH3 H3C CH3 C18H28OP2 CH FW 322.36 O P 3 P CH3 H3C H3C H3C

Fp: 230 °F 678562-100MG 100 mg 678562-500MG 500 mg 668524-100MG 100 mg 668524-500MG 500 mg 1,2-Bis[(2R,5R)-2,5-diethylphospholano]benzene(1,5- 8 668524-2G 2g cyclooctadiene)rhodium(I) tetrafluoroborate

DuPhos and BPE (R,R)-Et-DUPHOS-Rh (−)-1,2‑Bis((2S,5S)-2,5‑diisopropylphospholano)benzene H3C CH3 [228121‑39‑9] (S,S)-i-Pr-DUPHOS P CH3 C30H48BF4P2Rh Rh ‑ ‑ BF4 [147253 69 8] FW 660.36 P H3C CH C26H44P2 P 3 H C CH FW 418.58 CH3 3 3 P CH3 H3C CH3 698377-50MG 50 mg H3C 698377-250MG 250 mg

668176-100MG 100 mg 1,2-Bis[(2S,5S)-2,5-diethylphospholano]benzene(1,5- 8 668176-500MG 500 mg cyclooctadiene)rhodium(I) tetrafluoroborate 668176-2G 2g (S,S)-Et-DUPHOS-Rh H3C CH3 [213343‑64‑7] 8 P 1,2-Bis[(2R,5R)-2,5-dimethylphospholano]benzene C30H48BF4P2Rh - Rh BF4 monooxide FW 660.36 P

R,R-Me-BozPhos; (2R,5R)-1-{2-[(2R,5R)-2,5-Dimethylphos- H3C CH3 H C pholan-1-yl]phenyl}-2,5-dimethylphospholane 1-oxide 3 P CH3 [638132‑66‑8] 698385-50MG 50 mg O C18H28OP2 698385-250MG 250 mg FW 322.36 P CH3 H3C 1,2-Bis[(2R,5R)-2,5-diethylphospholano]benzene(1,5- 8 678635-100MG 100 mg cyclooctadiene)rhodium(I) trifluoromethanesulfonate 678635-500MG 500 mg (R,R)-Et-DUPHOS-Rh H3C CH3 [136705‑77‑6] P - C31H48F3O3P2RhS Rh CF3SO3 FW 722.62 P

H3C CH3 L R: 36/37/38 S: 26-36/37 698393-50MG 50 mg 698393-250MG 250 mg

1,2-Bis[(2S,5S)-2,5-diethylphospholano]benzene(1,5- 8 cyclooctadiene)rhodium(I) trifluoromethanesulfonate (S,S)-Et-DUPHOS-Rh H3C CH3 [142184‑30‑3] P C31H48F3O3P2RhS - Rh CF3SO3 FW 722.62 P

H3C CH3 L R: 36/37/38 S: 26 698407-50MG 50 mg Got ChemNews? 698407-250MG 250 mg A Monthly Chemistry E-Newsletter from Sigma-Aldrich® sigma-aldrich.com/chemnews

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1,2-Bis[(2R,5R)-2,5-diisopropylphospholano]benzene 8 1,2‑Bis[(2S,5S)-2,5‑dimethylphospholano]benzene(cycloocta- (1,5-cyclooctadiene)rhodium(I) tetrafluoroborate diene)rhodium(I) trifluoromethanesulfonate, 97% [569650‑64‑2] [136705‑75‑4] H3C CH3 O C H BF P Rh H C C H F O P RhS CH3 24 56 4 2 3 27 40 3 3 2 H3C P CH3 S FW 596.36 P FW 666.52 Rh F3C O

O BPE and DuPhos Rh BF 4 P H3C P CH3 CH3 H3C CH3 H3C L R: 36/37/38 S: 26-36/37 698342-50MG 50 mg 675563-100MG 100 mg 698342-250MG 250 mg 675563-500MG 500 mg

8 1,2-Bis[(2S,5S)-2,5-diisopropylphospholano]benzene (+)-1,2‑Bis((2R,5R)-2,5‑diethylphospholano)ethane (1,5-cyclooctadiene)rhodium(I) tetrafluoroborate (R,R)-Et-BPE C H BF P Rh CH3 34 56 4 2 H C H3C 3 CH [136705‑62‑9] FW 716.47 3 P H3C C H P P CH3 18 36 2 Rh BF FW 314.43 4 P P CH3 H3C H3C CH3 CH3 H3C Fp: 110 °C (230 °F) 698334-50MG 50 mg 668478-100MG 100 mg 698334-250MG 250 mg 668478-500MG 500 mg 668478-2G 2g 1,2‑Bis[(2R,5R)-2,5‑dimethylphospholano]benzene(cyclooctadiene)rhodium(I) tetrafluoroborate (−)-1,2‑Bis((2S,5S)-2,5‑diethylphospholano)ethane [210057‑23‑1] (S,S)-Et-BPE H3C CH3 C26H40BF4P2Rh H3C CH3 ‑ ‑ P [136779 27 6] P FW 604.25 Rh BF4 C18H36P2 P FW 314.43 H3C CH3 P H3C CH3 675520-100MG 100 mg J R: 17 S: 6 675520-500MG 500 mg 668451-100MG 100 mg 1,2‑Bis[(2S,5S)-2,5‑dimethylphospholano]benzene(cycloocta- 668451-500MG 500 mg diene)rhodium(I) tetrafluoroborate 668451-2G 2g [205064‑10‑4] 1,2‑Bis((2R,5R)-2,5‑diisopropylphospholano)ethane C H BF P Rh H3C CH3 26 40 4 2 P FW 604.25 Rh BF4 C22H44P2 CH3 P FW 370.53 H3C H3C CH3 P H3C CH3

H C CH3 3 P CH 675539-100MG 100 mg H3C 3 675539-500MG 500 mg 668443-100MG 100 mg ‑ ‑ 1,2 Bis[(2R,5R)-2,5 dimethylphospholano]benzene(cycloocta- 668443-500MG 500 mg ≥ diene)rhodium(I) trifluoromethanesulfonate, 97% 668443-2G 2g

H3C CH3 P OO 1,2‑Bis((2S,5S)-2,5‑diisopropylphospholano)ethane Rh S F3C O P C22H44P2 CH3 H3C CH3 FW 370.53 H3C P H3C CH3 ‑ ‑ H C CH3 [187682 63 9] 3 P CH3 C27H40F3O3P2RhS H3C FW 666.52

675571-100MG 100 mg 668435-100MG 100 mg 675571-500MG 500 mg 668435-500MG 500 mg 668435-2G 2g

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(+)-1,2‑Bis((2R,5R)-2,5‑dimethylphospholano)ethane 1,2‑Bis[(2S,5S)-2,5‑dimethylphospholano]ethane(cyclooctadiene)rhodium(I) tetrafluoroborate (R,R)-Me-BPE ‑ ‑ ‑ ‑ [129648 07 3] H3C P CH3 [213343 65 8] C H P C H BF P Rh H3C CH3 14 28 2 22 40 4 2 P FW 258.32 FW 556.21 Rh BF4 H C P CH 3 3 P H3C CH3

R: 11-17 J L R: 36/37/38 S: 26 665231-100MG 100 mg 675547-100MG 100 mg 665231-500MG 500 mg 675547-500MG 500 mg 665231-2G 2g 1,2-Bis[(2R,5R)-2,5-diphenylphospholano]ethane(1,5- 8 (−)-1,2‑Bis((2S,5S)-2,5‑dimethylphospholano)ethane cyclooctadiene)rhodium(I) tetrafluoroborate DuPhos and BPE (S,S)-Me-BPE (R,R)-Ph-BPE-Rh [136779‑26‑5] H C CH 3 P 3 [528565‑84‑6] Ph Ph C14H28P2 P C42H48BF4P2Rh Rh FW 258.32 BF4 H C P CH FW 804.49 P 3 3 Ph Ph

J R: 11-17 L R: 36/37/38 S: 26-36/37 665207-100MG 100 mg 698350-50MG 50 mg 665207-500MG 500 mg 698350-250MG 250 mg 665207-2G 2g 1,2-Bis[(2S,5S)-2,5-diphenylphospholano]ethane(1,5- 8 (−)-1,2‑Bis((2R,5R)-2,5‑diphenylphospholano)ethane cyclooctadiene)rhodium(I) tetrafluoroborate [528565‑79‑9] (S,S)-Ph-BPE-Rh C H P C42H48BF4P2Rh Ph Ph 34 36 2 P P FW 506.60 FW 804.49 Rh BF4 P P Ph Ph

R: 36/37/38 S: 26 667811-100MG 100 mg L 667811-500MG 500 mg 698369-50MG 50 mg 667811-2G 2g 698369-250MG 250 mg

(+)-1,2‑Bis((2S,5S)-2,5‑diphenylphospholano)ethane 1,1′-Bis((2R,5R)-2,5‑diethylphospholano)ferrocene R,R-Et-Ferrocelane™ [824395‑67‑7] CH3 C H P C26H40FeP2 34 36 2 P FW 506.60 FW 470.39 H3C P Fe P P CH3

H3C 667854-100MG 100 mg

667854-500MG 500 mg 680990-100MG 100 mg 667854-2G 2g 680990-500MG 500 mg

1,2‑Bis[(2R,5R)-2,5-(dimethylphospholano]ethane(cycloocta- 1,1′-Bis((2S,5S)-2,5‑diethylphospholano)ferrocene diene)rhodium(I) tetrafluoroborate S,S-Et-Ferrocelane™ ‑ ‑ CH3 [305818 67 1] C26H40FeP2 C22H40BF4P2Rh H3C CH3 P FW 470.39 H3C P FW 556.21 Rh BF 4 Fe P H C CH P 3 3 CH3

H C L R: 36/37/38 S: 26 3 675555-100MG 100 mg 681008-100MG 100 mg 675555-500MG 500 mg 681008-500MG 500 mg

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1,1′-Bis[(2R,5R)-2,5-diisopropylphospholano]ferrocene 8 (2S,5S)-(–)-1-(2-(1,3-Dioxolan-2-yl)phenyl)-2,5-diethyl- 8 phospholane C30H48FeP2 CH3 FW 526.49 H3C S,S-Et-RajPhos™ O C17H25O2P P O CH3 FW 292.35 H3C uhsadBPE and DuPhos Fe CH3 CH3 H3C P P H3C

CH3 H3C Fp: 230 °F 677078-100MG 100 mg 684309-100MG 100 mg 677078-500MG 500 mg 684309-500MG 500 mg (2R,5R)-1-(2-(1,3-Dioxolan-2-yl)phenyl)-2,5-dimethyl- 8 1,1′-Bis[(2S,5S)-2,5-diisopropylphospholano]ferrocene 8 phospholane C H FeP 30 48 2 CH R,R-Me-RajPhos™ FW 526.49 3 O H3C C15H21O2P FW 264.30 O P CH CH3 H C 3 3 Fe P CH3 H C P 3 H3C

CH3 Fp: 110 °C (230 °F) H3C 677043-100MG 100 mg 677043-500MG 500 mg 684406-100MG 100 mg 684406-500MG 500 mg (2S,5S)-(+)-1-(2-(1,3-Dioxolan-2-yl)phenyl-2,5- 8 dimethylphospholane 1,1′-Bis[(2R,5R)-2,5‑dimethylphospholano]ferrocene, 97+% S,S-Me-RajPhos™ R,R-Me-Ferrocelane™ O H3C C15H21O2P C22H32FeP2 FW 264.30 O FW 414.28 P CH3 CH3 Fe P H C P 3 H3C

CH3 Fp: 230 °F

675601-100MG 100 mg 677035-100MG 100 mg 675601-500MG 500 mg 677035-500MG 500 mg

1,1′-Bis[(2S,5S)-2,5‑dimethylphospholano]ferrocene DuPhos/BPE Ligands Kit I 8 S,S-Me-Ferrocelane™ Components H3C − ‑ ‑ C22H32FeP2 ( )-1,2 Bis((2S,5S)-2,5 dimethylphospholano)ethane (Aldrich 665207) 100mg FW 414.28 P (+)-1,2‑Bis[(2S,5S)-2,5‑dimethylphospholano]benzene (Aldrich 665266) 100mg CH 3 Fe (+)-1,2‑Bis((2S,5S)-2,5‑diphenylphospholano)ethane (Aldrich 667854) 100mg H3C − ‑ ‑ P ( )-1,2 Bis((2S,5S)-2,5 diisopropylphospholano)benzene (Aldrich 668176) 100mg 1,2‑Bis((2S,5S)-2,5‑diisopropylphospholano)ethane (Aldrich 668435) 100mg

CH3 (−)-1,2‑Bis((2S,5S)-2,5‑diethylphospholano)ethane (Aldrich 668451) 100mg (+)-1,2‑Bis[(2S,5S)-2,5‑diethylphospholano]benzene (Aldrich 668486) 100mg 1,1′-Bis[(2S,5S)-2,5‑dimethylphospholano]ferrocene (Aldrich 675598) 100mg 675598-100MG 100 mg (2S,5S)-(+)-1-(2-(1,3‑Dioxolan-2‑yl)phenyl-2,5‑dimethylphospholane (Aldrich 675598-500MG 500 mg 677035) 100mg 1,2‑Bis[(2S,5S)-2,5‑dimethylphospholano]benzene monooxide (Aldrich 678562) (2R,5R)-(+)-1-(2-(1,3-Dioxolan-2-yl)phenyl)-2,5-diethyl- 8 100mg ′ ‑ phospholane 1,1 -Bis((2S,5S)-2,5 diethylphospholano)ferrocene (Aldrich 681008) 100mg 1,1′-Bis[(2S,5S)-2,5‑diisopropylphospholano]ferrocene (Aldrich 684406) 100mg R,R-Et-RajPhos™ R: 11-17 O J C17H25O2P O FW 292.35 687774-1KT 1 kit CH3 P H3C

Fp: 230 °F 677051-100MG 100 mg 677051-500MG 500 mg

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catASium®—Essential Elements for Asymmetric Hydrogenations

R R Renat Kadyrov, Jürgen Krauter O catASium® / Rh O Evonik Degussa GmbH, Rodenbacher Chaussee 4, D-63457 Hanau-Wolfgang, Germany O O OR' OR' Transition metal catalyzed enantioselective hydrogenation has been O O ® established as one of the most favorable strategies for the synthesis of Catalyst R R’ Solvent TON ee (%) optically active compounds in academia and on the industrial scale. In ® particular, chiral ligands bearing trivalent phosphorus as the ligating catASium M(R)Rh H Me CH2Cl2 10,000 99 “ “ atom for soft metals like rhodium(I), ruthenium(II), or iridium(I) play a catASium® M(R)Rh H H CH Cl 4,000 99 pivotal role in this area. Among electron-rich chiral phosphines, chiral 2 2 phospholanes have emerged as one of the most efficient classes of catASium® MN(R)Rh Ph H Acetone 500 98 catASium ligands in metal catalyzed enantioselective reactions. Prominent catASium® MNBn(R)Rh i-Pr H CH OH 500 98 examples are bisphospholane ligands like DuPHOS and BPE. In general, 3 these compounds are synthesized by a linear approach, where the Table 1. Hydrogenation of β-substituted itaconic acid derivatives phospholane is constructed by condensation of a primary phosphine with the sulfate or sulfonates derived from the appropriate chiral diols in the presence of strong bases. This tedious approach is restricted by low tolerance of the functional groups and, therefore, strongly limits the NHAc catASium® / Rh NHAc possible variations of the backbone. COOR' COOR' R R (S) Evonik Degussa GmbH has developed a modular synthesis of diverse arrays of chiral vicinal bisphospholanes in collaboration with the Catalyst Conﬁ guration R R’ Solvent ee (%) 1 Leibniz-Institute of Organic Catalysis in Rostock. These ligands, which catASium® M(R)Rh E Me Bn CH Cl 99.5 are now commercially available on a multikilogram scale under the 2 2 ® trademark catASium M, are characterized by varied “bite-angle” and catASium M(R)Rh Z Me Bn CH3OH 89.9 2 electronic properties of the bridging unit. The new ligands can be catASium® M(R)Rh Ei-Pr Et CH Cl 99.7 advantageously employed in the fine-tuning of those enantioselective 2 2 ® hydrogenations, where the results obtained with traditional catASium M(R)Rh Zi-Pr Et CH2Cl2 89.6

bisphospholane ligands require optimization. ® catASium T2(R)/Rh E Me Me CH3OH 99.3 A rhodium(I) catalyst based on the new chiral bisphospholane ligand is ® one of the most effective catalytic systems for the hydrogenation of catASium T2(R)/Rh Z Me Me CH2Cl2 94 non-substituted and β-substituted itaconic acid derivatives known.3 The selected results (Table 1) show that this ligand displays a higher Table 2. Enantioselective hydrogenations ® performance as compared to the known systems. The excellent of β-enamides using catASium ligands enantioselectivities (up to 99%) are combined with a high catalytic activity (TOF up to 40,000 h-1). Exciting results were also observed in the hydrogenation of β-acylamido NHAc catASium® / Rh NHAc

acrylates (Table 2). These are important intermediates in the synthesis of R R (R) enantiopure β-amino acids. Particularly, when the hydrogenation of the challenging Z-configured substrates bearing bulky substituents in the R ligand Solvent ee (%) ‑ 3 position (for example i-Pr) were tested, a catASium M(R)Rh-catalyst t-Bu catASium® T1 CH Cl 87 showed the highest enantioselectivities known for these substrates. 2 2 A new class of atropisomeric ligands based on camphor catASium T were Ph catASium® T2 MeOH 92 developed in close collaboration with Russian researchers. The new 3-NO C H catASium® T2 toluene 99.7 ligand system combines the features of central chirality derived from a 2 6 4 natural product with axial chirality like in the biaryl type ligands. In 2-naphthyl catASium® T2 toluene 98 addition to this, the two phosphorus groups are introduced sequentially leading to a large variety of tuneable ligands.4 Table 3. Enantioselective hydrogenation of enamides using Rh(I)-complexes of catASium® T The selected results of hydrogenation of (Z)- and (E)-methyl 3‑acetylamino-2‑butenoates are summarized in Table 2. Excellent enantiomeric excesses of >99% were reached by hydrogenation of the E-isomer. Noteworthy is the 94% ee achieved using catASium T2 catalyst O catASium® D(R)Rh NHBn

in the hydrogenation of the Z-isomer. It is one of the best optical R COOH BnNH , H R (S) COOH inductions achieved in the hydrogenation of the Z-β-enamides. These 2 2 ligands also show interesting properties in the hydrogenation of R Product Isolated Yield ee (%) challenging simple α-enamides (Table 3). Me N-Bn-Ala 43 78 Whereas applying catalysts based on catASium T ligands to electron-rich substrates induce only moderate enantiomeric excesses, the PhCH2 N-Bn-Phe 99 98 hydrogenation of the substrate with electron-withdrawing groups PhCH2CH2 N-Bn-Bn-Ala 79 81 surprisingly leads to near complete enantioselectivity. Me CHCH N-Bn-Leu 99 90 Cationic catalyst catASium DRh, with a ligand well known under the 2 2 old name Deguphos, was successfully utilized in the first highly Me3CCH2 N-Bn-t-Bu-Ala 94 86 enantioselective reductive amination of keto acids, where several chiral α-amino acids were produced in good yield and very high ee's Table 4. Yields and enantioselectivities of the reductive amination (up to 98%) (Table 4).5 of α-keto acids with benzylamine using catASium® D(R)Rh

References: (1) Holz, J.; Monsees, A.; Jiao, H.; You, J.; Komarov, I. V.; Fischer, C.; Drauz, K.; Börner, A. J. Org. Chem. 2003, 68, 1701‑1707. (2) Holz, J.; Zayas, O.; Jiao, H.; Baumann, W.; Spannenberg, A.; Monsees, A.; Riermeier, T. H.; Almena, J.; Kadyrov, R.; Börner, A. Chem. -Eur. J. 2006, 12, 5001‑5013. (3) Almena, J.; Monsees, A.; Kadyrov, R.; Riermeier, T. H.; Gotov, B.; Holz, J.; Börner, A. Adv. Synth. Catal. 2004, 346, 1263‑1266. (4) Kadyrov, R.; Ilaldinov, I. Z.; Almena, J.; Monsees, A.; Riermeier, T. H. Tetrahedron Lett. 2005, 46, 7395‑7400. (5) Kadyrov, R.; Riermeier, T. H.; Dingerdissen, U.; Tararov, V.; Börner, A. J. Org. Chem. 2003, 68, 4067‑4070.

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D-type (−)-2,3-Bis[(2R,5R)-2,5-dimethylphospholano]-N-[3,5- 8 bis(trifluoromethyl)phenyl]maleimide(1,5-cycloocta- (+)-N-Benzyl-(3R,4R)-bis(diphenylphosphino) 8 diene)rhodium(I) tetrafluoroborate, 98% pyrrolidine, 98% 3,4-Bis[(2R,5R)-2,5-dimethylphospholanyl]-1- BF - H3C CH3 4 [3,5-di(trifluoromethyl)phenyl]-1H-pyrrol-2,5- O CF3 (+)-(3R,4R)-3,4-Bis(diphenylphosphino)-1-benzyl- P catASium dion(1,5-cyclooctadiene)rhodium(I) tetra- pyrrolidine; (3R,4R)-1-Benzyl-3,4-bis-diphenylphos- + ® Rh N phanyl-pyrrolidine; catASium® D(R) fluoroborate; catASium MNXylF(R)Rh P P P O C32H39BF10NO2P2Rh CF3 [99135‑95‑2] H3C CH FW 835.31 3 C35H33NP2 N FW 529.59 ≥98% (31P-NMR) ® 670154-100MG 100 mg 670154-500MG 500 mg ≥98% (31P-NMR) R: 36 S: 26 L (−)-4,5-Bis[(2R,5R)-2,5-dimethylphospholano]-1,2-di- 8 672653-100MG 100 mg hydro-1,2-dimethyl-3,6-pyridazinedione(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate, 95% 672653-500MG 500 mg

{4,5-Bis[(2R,5R)-2,5-dimethylphospholanyl]- CH H C 3 8 3 O (+)-1-Benzyl-[(3R,4R)-bis(diphenylphosphino)] 1,2-dimethyl-1,2-dihydropyridazine-3,6- P CH3 dione}(1,5-cyclooctadiene)rhodium(I) tetra- N BF4 pyrrolidine(1,5-cyclooctadiene)rhodium(I) tetra- Rh ® N fluoroborate, 98% fluoroborate; catASium MNN(R)Rh CH3 [908128‑78‑9] P O H3C (3R-trans)-3,4-Bis(diphenylphosphino)-1- CH3 C26H42BF4N2O2P2Rh (phenylmethyl)pyrrolidine rhodium complex; FW 666.28 ® P 31 catASium D(R)Rh BF4 ≥95% ( P-NMR) ‑ ‑ Rh N [99143 48 3] 670588-100MG 100 mg C43H45BF4NP2Rh P FW 827.48 670588-500MG 500 mg

2,3-Bis[(2R,5R)-2,5-dimethylphospholano]-N-(3,5- 8 ≥ 31 98% ( P-NMR) dimethylphenyl)maleimide, 98% R: 36/37/38 S: 26 L 3,4-Bis[(2R,5R)-2,5-dimethylphospholanyl]-1-(3,5- CH3 ® 672777-100MG 100 mg O CH3 dimethylphenyl)-1H-pyrrol-2,5-dione; catASium P 672777-500MG 500 mg MNXyl(R) H3C N C24H33NO2P2 H3C P FW 429.47 O CH3 M-type CH3

2,3-Bis[(2R,5R)-2,5-dimethylphospholano]-N-benzyl- 8 ≥98% (31P-NMR) maleimide(1,5-cyclooctadiene)rhodium(I) tetrafluoro- 669814-100MG 100 mg borate, 95% 669814-500MG 500 mg 3,4-Bis[(2R,5R)-2,5-dimethylphospholanyl]-1- - H3C CH3 BF4 − 8 benzyl-1H-pyrrol-2,5-dion(1,5-cyclooctadiene) P O ( )-2,3-Bis[(2R,5R)-2,5-dimethylphospholano]-N-(3,5- rhodium(I) tetrafluoroborate; catASium® MNBn dimethylphenyl)maleimide(1,5-cyclooctadiene)rhodi- Rh+ N (R)Rh um(I) tetrafluoroborate, 95% P O C31H43BF4NO2P2Rh H3C CH3 3,4-Bis[(2R,5R)-2,5-dimethylphospholanyl]-1- FW 713.34 BF - H3C CH3 4 (3,5-dimethylphenyl]-1H-pyrrol-2,5-dion(1,5- P O CH3 ≥95% (31P-NMR) cyclooctadiene)rhodium(I) tetrafluoroborate; Rh+ N R: 36/37/38 S: 26 catASium® MNXyl(R)Rh L P O C32H45BF4NO2P2Rh CH3 H3C CH3 669709-100MG 100 mg FW 727.36 669709-500MG 500 mg ≥95% (31P-NMR) R: 36/37/38 S: 26 2,3-Bis[(2R,5R)-2,5-dimethylphospholano]-N-[3,5-bis 8 L (trifluoromethyl)-phenyl]maleimide, 98% 669938-100MG 100 mg 3,4-Bis[(2R,5R)-2,5-dimethylphospholanyl]-1-[3,5- 669938-500MG 500 mg CH3 O CF bis(trifluormethyl)phenyl]-1H-pyrrol-2,5-dione; P 3 ® catASium MNXylF(R) H3C N C24H27F6NO2P2 H3C P FW 537.41 O CF3 CH3

≥98% (31P-NMR) L R: 36/37/38 S: 26 670030-100MG 100 mg 670030-500MG 500 mg

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(−)-2,3-Bis[(2R,5R)-2,5-dimethylphospholano]maleic 8 (−)-2,3-Bis[(2R,5R)-2,5-dimethylphospholano]-N- 8 anhydride, 98% methylmaleimide(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate, 98% 3,4-Bis[(2R,5R)-2,5-dimethyl-1-phospholanyl]furan-2,5- CH3 ® O dione; catASium M(R) P 2,3-Bis[(2R,5R)-2,5-dimethylphospholanyl] H3C CH [505092‑86‑4] H C malein-N-methylimide(1,5-cyclooctadiene) 3 3 O P O - H3C ® BF4

® C16H24O3P2 rhodium(I) tetrafluoroborate; catASium MN(R) P Rh+ N CH FW 326.31 O Rh 3 CH3 [821793‑41‑3] P O H3C CH3 ≥ 31 C25H39BF4NO2P2Rh 98% ( P-NMR) FW 637.24 670693-100MG 100 mg ≥98% (31P-NMR)

catASium 670693-500MG 500 mg L R: 36/37/38 S: 26

(−)-2,3-Bis[(2R,5R)-2,5-dimethylphospholano]maleic 8 669598-100MG 100 mg anhydride(1,5-cyclooctadiene)rhodium(I) tetrafluoro- 669598-500MG 500 mg borate, 98% 2,3-Bis[(2R,5R)-2,5-dimethylphospholano]-N-(penta- 8 2,3-Bis[(2R,5R)-2,5-dimethyl-phospholanyl]maleic H C fluorophenyl)maleimide(1,5-cyclooctadiene)rhodium anhydride(1,5-cyclooctadiene)rhodium(I) tetra- 3 CH3 P O (I) tetrafluoroborate, 95% fluoroborate; catASium® M(R)Rh Rh O [507224‑99‑9] BF4 P H3C CH3 C H BF O P Rh O F F BF4 24 36 4 3 2 H C CH P O FW 624.20 3 3 Rh+ N F ≥ 31 98% ( P-NMR) P O F F H3C CH3 670804-100MG 100 mg 670804-500MG 500 mg 3,4‑Bis[(2R,5R)-2,5‑dimethylphospholanyl]-1‑pentafluorophenyl-1H- pyrrole-2,5‑dione(1,5‑cyclooctadiene)rhodium(I) tetrafluoroborate; − 8 ( )-2,3-Bis[(2R,5R)-2,5-dimethylphospholano]-N-(4- catASium® MNF(R)Rh methoxyphenyl)maleimide(1,5-cyclooctadiene)rhodi- C30H36BF9NO2P2Rh um(I) tetrafluoroborate, 98% FW 789.26 ≥95% (31P-NMR) - H C BF4 3 CH3 670367-100MG 100 mg P O

+ 670367-500MG 500 mg Rh N OCH3 P O 8 H3C CH3 1,2-Bis[(2R,5R)-2,5-dimethylphospholano]-3,3,4,4- tetrafluoro-1-cyclobutene(1,5-cyclooctadiene)rhodi- 3,4‑Bis[(2R,5R)-2,5‑dimethylphospholanyl]-1-(4‑methoxyphenyl)-1H- um(I) ) tetrafluoroborate, 95% ‑ ‑ pyrrol-2,5 dion(1,5 cyclooctadiene)rhodium(I) tetrafluoroborate; 1,2-Bis[(2R,5R)-2,5-dimethyl-phospholanyl] ® catASium MNAn(R)Rh H3C CH3 3,3,4,4-tetrafluoro-1-cyclobutene(1,5-cyclo- P F C31H43BF4NO3P2Rh F octadiene)rhodium(I) tetrafluoroborate; + - FW 729.34 ® Rh BF4 catASium MQF(R)Rh F ≥98% (31P-NMR) [910048‑20‑3] P F H3C CH3 670251-100MG 100 mg C24H36BF8P2Rh 670251-500MG 500 mg FW 652.19 ≥95% (31P-NMR) 670472-100MG 100 mg 670472-500MG 500 mg

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T-type Kit

(1R,aR)-3-Diphenylphosphino-2-(4-bis(3,5-dimethyl- 8 Evonik Ligand Kit for Asymmetric Hydrogenations 8 phenyl)phosphino-2,5-dimethyl-3-thienyl)-1,7,7-tri- catASium® Ligand Toolbox methylbicyclo[2.2.1]hept-2-ene, 99% catASium 3-[Bis(3,5-dimethylphenyl)phosphanyl]-4- [(1R,4S)-3-diphenylphosphanyl-1,7,7-trimethyl- CH3 H3C bicyclo[2.2.1]hept-2-en-2-yl]-2,5-dimethylthio- H P phene; catASium® T3(R) ‑ ‑ CH3 [868851 50 7] CH3 CH3

C44H48P2S ® S FW 670.86 H3C P CH3

H3C CH3

≥99% (31P-NMR) 671258-100MG 100 mg 671258-500MG 500 mg

(1R,aR)-3-[Bis(3,5-dimethylphenyl)phosphino]-2-(4- 8 diphenylphosphino-2,5-dimethyl-3-thienyl)-1,7,7-trimethylbicyclo[2.2.1]hept-2-ene, 99% 3-{(1R,4S)-3-[Bis(3,5-dimethylphenyl)phospha- H3C CH3 nyl]-1,7,7-trimethylbicyclo[2.2.1]hept-2-en-2-yl}- CH3 H3C 4-diphenylphosphanyl-2,5-dimethylthiophene; H catASium® T2(R) P CH3 [868851‑48‑3] CH CH C H P S 3 3 44 48 2 CH3 S FW 670.86 P

CH3

≥99% (31P-NMR) Components 671142-100MG 100 mg (+)-N-Benzyl-(3R,4R)-bis(diphenylphosphino)pyrrolidine (Aldrich 672653) 671142-500MG 500 mg (+)-1‑Benzyl-[(3R,4R)-bis(diphenylphosphino)]pyrrolidine(1,5‑cyclooctadiene)rhodium(I) tetrafluoroborate (Aldrich 672777) ‑ ‑ ‑ ‑ (1R,aR)-3-Diphenylphosphino-2-(4-diphenylphos- 8 (1R,aR)-3 Diphenylphosphino-2-(4 bis(3,5 dimethylphenyl)phosphino-2,5 dimethyl- 3‑thienyl)-1,7,7‑trimethylbicyclo[2.2.1]hept-2‑ene (Aldrich 671258) phino-2,5-dimethyl-3-thienyl)-1,7,7-trimethyl-bicyclo (1R,aR)-3-[Bis(3,5‑dimethylphenyl)phosphino]-2-(4‑diphenylphosphino-2,5‑dimeth- [2.2.1]hept-2-en, 99% yl-3‑thienyl)-1,7,7‑trimethylbicyclo[2.2.1]hept-2‑ene (Aldrich 671142) ‑ ‑ ‑ ‑ 3-Diphenylphosphanyl-4-[(1R,4S)-3-diphenylphospha- (1R,aR)-3 Diphenylphosphino-2-(4 diphenylphosphino-2,5 dimethyl-3 thienyl)- 1,7,7‑trimethyl-bicyclo[2.2.1]hept-2‑en (Aldrich 671029) nyl-1,7,7-trimethylbicyclo[2.2.1]hept-2-en-2-yl]-2,5- CH3 (−)-2,3‑Bis[(2R,5R)-2,5‑dimethylphospholano]maleic anhydride(1,5‑cyclooctadiene) ® H3C dimethylthiophene; catASium T1(R) H P rhodium(I) tetrafluoroborate (Aldrich 670804) [868851‑47‑2] (−)-2,3‑Bis[(2R,5R)-2,5‑dimethylphospholano]maleic anhydride (Aldrich 670693) C40H40P2S (−)-4,5‑Bis[(2R,5R)-2,5‑dimethylphospholano]-1,2‑dihydro-1,2‑dimethyl-3,6‑pyrida- CH3 CH3 FW 614.76 zinedione(1,5‑cyclooctadiene)rhodium(I) tetrafluoroborate (Aldrich 670588) S P 1,2‑Bis[(2R,5R)-2,5‑dimethylphospholano]-3,3,4,4‑tetrafluoro-1‑cyclobutene(1,5‑cy-

CH3 clooctadiene)rhodium(I) ) tetrafluoroborate (Aldrich 670472) 2,3‑Bis[(2R,5R)-2,5‑dimethylphospholano]-N-(pentafluorophenyl)maleimide(1,5‑cyclooctadiene)rhodium(I) tetrafluoroborate (Aldrich 670367) − ‑ ‑ ‑ ≥ 31 ( )-2,3 Bis[(2R,5R)-2,5 dimethylphospholano]-N-(4 methoxyphenyl)maleimide 99% ( P-NMR) (1,5‑cyclooctadiene)rhodium(I) tetrafluoroborate (Aldrich 670251) 671029-100MG 100 mg (−)-2,3‑Bis[(2R,5R)-2,5‑dimethylphospholano]-N-[3,5‑bis(trifluoromethyl)phenyl]mal- ‑ 671029-500MG 500 mg eimide(1,5 cyclooctadiene)rhodium(I) tetrafluoroborate (Aldrich 670154) 2,3‑Bis[(2R,5R)-2,5‑dimethylphospholano]-N-[3,5‑bis(trifluoromethyl)-phenyl]maleimide (Aldrich 670030) (−)-2,3‑Bis[(2R,5R)-2,5‑dimethylphospholano]-N-(3,5‑dimethylphenyl)maleimide (1,5‑cyclooctadiene)rhodium(I) tetrafluoroborate (Aldrich 669938) 2,3‑Bis[(2R,5R)-2,5‑dimethylphospholano]-N-(3,5‑dimethylphenyl)maleimide (Al- drich 669814) 2,3‑Bis[(2R,5R)-2,5‑dimethylphospholano]-N-benzylmaleimide(1,5‑cyclooctadiene) rhodium(I) tetrafluoroborate (Aldrich 669709) (−)-2,3‑Bis[(2R,5R)-2,5‑dimethylphospholano]-N-methylmaleimide(1,5‑cyclooctadiene)rhodium(I) tetrafluoroborate (Aldrich 669598) L R: 36/37/38 S: 26 672556-1KT 1 kit

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P-Phos, PhanePhos and BoPhoz™ Ligands

* OH O O O [L -Ru(C6H6)Cl]Cl OCH3 1 2 R1 OR2 R * OR N EtOH/CH2Cl2 4 - 25 atm H2 H CO PAr 3 2 70 - 90 oC, 1-24 h H3CO PAr2 OH O OH O OH O N ClH C OC H H3C * OC2H5 H3C * OCH2Ph 2 * 2 5

OCH3 (S)-P-Phos S/C 400, 98.6% ee S/C 2800, 96.6% ee S/C 2800, 98.0% ee

Ligands (R)-Tol-P-Phos S/C 400, 98.0% ee S/C 400, 98.0% ee S/C 400, 97.9% ee P-Phos (R)-Xyl-P-Phos S/C 400, 97.1% ee S/C 2800, 94.5% ee S/C 400, 94.8% ee ™ The P-Phos ligand family was developed by Professor Chan of Hong Scheme 1 Kong Polytechnic University and licensed to JM CCT in 2002. P-Phos is an atropisomeric biaryl bisphosphine with the unique feature of incorporating two methoxy-substituted pyridine rings in the backbone.1 [L*-Ru(C H )Cl]Cl, 1 atm H CO2Me BoPhoz 6 6 2 This family of ligands often presents higher activity and selectivity than R NHCOMe the analogous BINAP ligands in a series of reactions such as ruthenium MeOH, rt, 3-10 h, S/C 100 catalyzed hydrogenation of β-ketoesters2 (Scheme 1) and rhodium- and CO2Me R NHCOMe * ruthenium-catalyzed hydrogenation of dehydroamino acids [L -Rh(COD)]BF4, 1 atm H2 CO2Me P-Phos, PhanePhos and 3 R (Scheme 2). Ru catalyzed hydrogenation of non-functionalized NHCOMe ketones is also highly effective using P-Phos ligands.4 Moreover, JM MeOH, 0 oC, 18 h, S/C 100 Cl has further developed the scope of P-Phos Ru diamine complexes in CO2Me CO2Me CO2Me ketone hydrogenation by the application of less traditional 1,3- and NHCOMe NHCOMe 1,4‑diamines (Scheme 3).5 Iridium-P-Phos catalysts have been NHCOMe Me MeO recently used for the asymmetric hydrogenation of C=N bonds in Ru-(R)-P-Phos 97% ee 91% ee 90% ee quinolines (Scheme 4).6 Rh-(R)-Xyl-P-Phos 90% ee 94% ee 90% ee Scheme 2 PAr2

PAr2 O RuCl2[(R)-Xyl-P-Phos][(R,R)-DPEN] OH Phanephos 1 R R R * R1 2-propanol, KOtBu Phanephos was first reported in 1997, and since then it has found rt, 6 - 55 atm H2, 2 - 48 h X S/C ee applications in the rhodium-catalyzed hydrogenation of dehydroamino X OH 7 acids (Scheme 5) and the ruthenium-catalyzed hydrogenation of H 100,000 99.1 β-ketoesters (Scheme 6).8 Both rhodium and ruthenium catalysts Me 4000 97.7 OMe 4000 93.3 bearing the Phanephos ligand show an exceptionally high activity in most Br 10000 >99.9 homogeneous hydrogenation reactions. Scheme 3

[Ir(COD)Cl]2/(R)-P-Phos/I2

N R rt, 20 h, 47 atm H2, THF N R * H S/[Ir]/L /I2 = 100:0.5:1.1:10 F OH

N Me N Me N H H H ee 91% 90% 91% isolated yield 97% 90% 99%

Scheme 4

1 2 1 2 R1 R2 P ee (%) R R [(S)-Phanephos Rh]OTf R R H H Ac 99.6 (R) OMe OMe Ph H Ac 98 (R) PHN MeOH, 1.5 atm H2 PHN * O O Ph H Bz 97 (R) H H Cbz 91 (R)

Scheme 5

R = R' = Me 96% ee (R) O O OH (S)-Phanephos Ru(TFA)2 R = Me, R' = tBu 95% ee (R) ' R OR' R * OR R = Et, R' = Me 95% ee (R) Bu4NI, MeOH/H2O (10:1) 3.5 atm H2, 18 h R = iPr, R' = Et 95% ee (S)

Scheme 6

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CO2R' [(COD)2Rh]OTf, (R,S)-MeBoPhoz R CO2R' R R N NHR'' rt, THF, 10 psi H2 NHR'' Fe PR2 PR2

BoPhozTM CO Me CO Me CO2Me Ph CO Me Ph 2 Ph 2 2 NHAc NHAc NHBoc NC NHCbz The BoPhoz class of ligands, based on the ferrocene backbone, have BoPhoz and PhanePhos P-Phos, 99.1% ee 91.5% ee 99% ee 98.1% ee proven to be exceptionally active in many rhodium-catalyzed 9 hydrogenations as well as being used in a number of ruthenium- Scheme 7 catalyzed reactions. More recently Johnson-Matthey has developed new variants of BoPhoz ligands that offer increased structural and electronic diversity that may be required for the desired transformation. MeBoPhoz ™ CO2R' [(COD)2Rh]OTf, (R,S)-MeBoPhoz CO2R' has shown excellent activity in many rhodium-catalyzed asymmetric R R R = H, R' = H 97.6% ee Ligands R = H, R' = CH3 94% ee rt, MeOH, 300 psi H2 hydrogenation of C=C bonds in dehydroaminoacids and CO2R' CO2R' R = Ph, R' = H 90% ee α,β-unsaturated acids and esters (s/c up to 100,000) (Scheme 7).10

[(COD) Rh]OTf, (R,S)-MeBoPhoz The P-Cy-Me-BoPhoz ligand has been shown to catalyze the asymmetric R CO2R' 2 R CO2R' reduction of α-ketoesters, which is unusual for a rhodium catalyst O rt, 300 psi H2, S/C 1000:1 OH (Scheme 8). R R' Solvent TOF e e (%) Me References: (1) Wu, J.; Chan, A. S. C. Acc. Chem. Res., 2006, 39, 711. (2) Wu, J. et al. N CH3 CH3 9:1 EtOAc/THF 2100 86.6 PPh Tetrahedron Lett. 2002, 43, 1539. (3) Wu, J. et al. Tetrahedron: Asymmetry 2003, 14, 987. Fe 2 PPh2 CH3 CH3 MeOH 750 75.4 (4)(a) Wu, J. et al. J. Org. Chem. 2002, 67, 7908. (b) Wu, J. et al. Chem. -Eur. J. 2003, 9, CH3 CH2CH3 9:1 EtOAc/THF 4440 91.6 PhCH CH CH CH 9:1 EtOAc/THF 580 80.2 2963. (5)(a) Hems, W. P. et al. Acc. Chem. Res. 2007, 40, 1340. (b) Grasa, G. A. et al. J. 2 2 2 3 Organomet. Chem. 2006, 691, 2332. (c) Grasa, G. A. et al. Org. Lett. 2005, 7, 1449. Me N (6) Xu, L. et al. Chem. Commun. 2005, 1390. (7) Rossen, K. et al. J. Am. Chem. Soc. 1997, CH3 CH3 9:1 EtOAc/THF 3360 89.6 PPh2 119, 6207. (8) Pye, P. J. et al. Tetrahedron Lett. 1998, 39, 4441. (9)(a) Boaz, N.W. et al. Org. Fe PCy2 CH3 CH3 MeOH 2350 11.2 CH3 CH2CH3 9:1 EtOAc/THF 6220 91.6 Lett. 2002, 4, 2421. (b) Boaz, N.W. J. Org. Chem. 2005, 70, 1872. (10) Boaz, N.W. Org. PhCH2CH2 CH2CH3 9:1 EtOAc/THF 4370 90.2 Proc. Res. Dev. 2005, 9, 472. Scheme 8

(R)-(–)-4,12-Bis(diphenylphosphino)-[2.2]-paracyclo- 8 (R)-(–)-4,12-Bis[di(3,5-xylyl)phosphino]-[2.2]-para- 8 phane, 96% cyclophane, 97% (R)-Phanephos [364732‑88‑7] PPh2 C40H34P2 FW 576.65 PPh2 PR2 PR2

L R: 37 CH3 682144-100MG 100 mg R= CH3 682144-500MG 500 mg (R)-Xylyl-PHANEPhos; (R)- (S)-(+)-4,12-Bis(diphenylphosphino)-[2.2]-paracyclo- 8 5,11‑Bis(3,5‑xylylphosphino)tricyclo[8.2.2.24,7]hexadeca-hexaene phane, 96% [325168‑89‑6] (S)-Phanephos C48H50P2 FW 688.86 [192463‑40‑4] PPh2 R: 36/38 S: 26 C40H34P2 L FW 576.65 PPh2 682306-100MG 100 mg L R: 37 682306-500MG 500 mg 682136-100MG 100 mg (S)-(+)-4,12-Bis[di(3,5-xylyl)phosphino]-[2.2]-para- 8 682136-500MG 500 mg cyclophane, 97% (S)-xylyl-PHANEPHos; (S)-5,11-Bis(3,5-xylyl- 4,7 phosphino)tricyclo[8.2.2 ]hexadeca- PR2 hexaene [325168‑88‑5] PR2 C48H50P2 FW 688.86 CH3

R= CH3 L R: 36/38 S: 26 682292-100MG 100 mg 682292-500MG 500 mg

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(R)-N-Methyl-N-diphenylphosphino-1-[(S)-2-diphenyl- 8 (S)-(−)-2,2′,6,6′-Tetramethoxy-4,4′-bis(diphenylphosphino)- phosphino)ferrocenyl]ethylamine 3,3′-bipyridine, 97% Methyl-BoPhoz; (1R)-1-(Diphenylphosphino)-2-[(1R)- (S)-P-Phos OCH3 1-[(diphenylphosphino)methylamino]ethyl]ferrocene [362524‑23‑0] CH3 N [406680‑94‑2] P Fe C38H34N2O4P2 CH3 H CO PPh C37H35FeNP2 N FW 644.64 3 2 H CO PPh FW 611.47 P 3 2 N

OCH3 Ligands 682322-100MG 100 mg R: 37

™ L 682322-500MG 500 mg 675792-100MG 100 mg (S)-N-Methyl-N-diphenylphosphino-1-[(R)-2-(diphenyl- 8 675792-500MG 500 mg phosphino)ferrocenyl]ethylamine

BoPhoz (R)-(+)-2,2′,6,6′-Tetramethoxy-4,4′-bis(di(3,5‑xylyl)phos- Methyl-BoPhoz; (1S)-1-(Diphenylphosphino)-2- phino)-3,3′-bipyridine, 97% [(1S)-1-[(diphenylphosphino)methylamino]ethyl] H3C P (R)-Xylyl-P-Phos ferrocene H3C H3C CH3 N Fe ‑ ‑ P-Phos, PhanePhos and [406681‑09‑2] [442905 33 1] H CO CH3 P C46H50N2O4P2 3 C37H35FeNP2 FW 611.47 FW 756.85 N P

H3CO CH3 CH 682314-100MG 100 mg H3CO 3 682314-500MG 500 mg N P H CO 3 CH3 ′ ′ ′ (R)-(+)-2,2 ,6,6 -Tetramethoxy-4,4 -bis(diphenylphosphino)- H3C CH3 3,3′-bipyridine, 97% R: 36/37/38 S: 26 (R)-P-Phos L OCH3 [221012‑82‑4] N 676004-100MG 100 mg C38H34N2O4P2 676004-500MG 500 mg FW 644.64 H3CO PPh2 H3CO PPh2 N (S)-(−)-2,2′,6,6′-Tetramethoxy-4,4′-bis[di(3,5‑xylyl)phos- ′ OCH3 phino]-3,3 -bipyridine, 97% (S)-Xylyl-P-Phos H3C CH3 675806-100MG 100 mg [443347‑10‑2] H CO CH3 675806-500MG 500 mg C46H50N2O4P2 3 FW 756.85 N P

H3CO CH3 CH H3CO 3 N P

H CO 3 CH3

H3C CH3 L R: 36/37/38 S: 26-36 675946-100MG 100 mg 675946-500MG 500 mg

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ChiralQuest Phosphine Ligands and Complexes

Professor Xumu Zhang at Penn State has made remarkable advances by (1R,1'R,2S,2'S)-DuanPhos creating a toolbox of chiral phosphines which can be used on a variety of substrates, some of which have been historically resistant to facile DuanPhos is more rigid than the related TangPhos ligand, due to the iad n Complexes and Ligands Phosphine ChiralQuest hydrogenation. Furthermore, an additional benefit in some reductions is fused phenyl rings on the phospholane architecture. This self-imposed reduced catalyst loading, due to increased turnover numbers (TON).1 conformational stability improves the enantioselectivity in the hydrogenations of a diverse array of functionalized olefins. Furthermore, Zhang and co-workers have successfully synthesized both enantiomers of (S)-C3‑TunePhos this electron-rich ligand through a trivial resolution process. Even highly C3‑TunePhos, a member of the atropisomeric aryl bisphosphine ligand electron-rich prochiral olefins are readily hydrogenated with exceptional family with tunable dihedral angles, provides comparable or superior stereocontrol by this productive Rh-catalyst system (Scheme 8). enantioselectivities and catalytic abilities to BINAP in Ru-catalyzed asymmetric hydrogenation of β-keto esters (Scheme 1),2 cyclic References: (1) Zhang, W. et al. Acc. Chem. Res. 2007 40, 1278. (2) Zhang, Z. et al. J. Org. β-(acylamino) acrylates (Scheme 2),3 and α-phthalimide ketones Chem. 2000, 65, 6223. (3) Tang, W. et al. J. Am. Chem. Soc. 2003, 125, 9570. (4) Lei, A. et 4 al. J. Am. Chem. Soc. 2004, 126, 1626. (5) Tang, W.; Zhang, X. Angew. Chem., Int. Ed. (Scheme 3). Engl. 2002, 41, 1612. (6) Tang, W.; Zhang, X. Org. Lett. 2002, 4, 4159. (7) Tang, W. et al. Org. Lett. 2003, 5, 205. (8) Yang, Q. et al. Angew. Chem., Int. Ed. 2006, 45, 3832. S S R R (9) Tang, W. et al. Angew. Chem., Int. Ed. Engl. 2003, 42, 3509. (10) Xiao, D. et al. Org. (1 ,1 ',2 ,2 ')-TangPhos Lett. 1999, 1, 1679. (11) Corkey, B. K.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 2764. A highly electron-donating, low molecular weight, and rigid P-chiral bisphospholane ligand, TangPhos proved to be incredibly efficient in the rhodium-catalyzed hydrogenation of a variety of functionalized olefins such as α-dehydroamino acids,5 arylenamides,5 β-(acylamino)acrylates,6 itaconic acids,7 and N-tosylimines8 (Scheme 4). O PPh2 O PPh2 This P-chiral phosphorus ligand represents a superior ligand for C3-TunePhos asymmetric catalysis including hydrogenation because of its ability to OO OH O force the chiral environment to encompass the substrate in close Ru[(R)-C3-TunePhos]Cl2(DMF)n (0.5 mol %) o proximity to the reactive metal center. TangPhos exhibits substantial R1 OR2 MeOH, 60 C, 750 psi H2 R1 OR2 conformational rigidity allowing for high enantioselectivities in the Up to 99% ee hydrogenation of a wide variety of densely functionalized prochiral olefins, with some reaction examples approaching 100% ee. OO OH O Ru(ArH)[(R)-C3-TunePhos]Cl2 Cl * Cl o OEt EtOH, 100 C, 6 atm H2 OEt (S)-BINAPINE TON = 45,000 97% ee Lipitor Side Chain BINAPINE, a highly electron-donating rigid ligand, demonstrates excellent enantioselectivity and reactivity, with TON up to 10,000 for the Scheme 1 asymmetric hydrogenation of Z-β-aryl(β-acylamino) acrylates (Scheme 5).9 Interestingly, BINAPINE is a rare example of a

bisbinaphthophosphepine ligand with P-chiral phosphine atoms. High In-situ 5 mol% Ru(COD)(Met) 2 AcHN CO R enantioselectivities have been obtained with substrates that contain AcHN CO2R 5 mol% (S)-C3-TunePhos 2 diverse substituents ranging from electron-rich and electron-poor 10 mol% HBF4 X MeOH, 50 atm H2, rt X aryl groups to heteroaryl components. This catalyst system illustrates up to 99% ee the incredible effects of rigidity on the stereocontrol in the hydrogenation reaction. Scheme 2

(R)-BINAPHANE O HO O BINAPHANE incorporates a bisphosphinite backbone that displays O 2 mol% R R μ restricted orientation of the aromatic groups proximate to the [NMe2H2][[RuCl((S)-C3-TunePhos)]2( -Cl)3] N N phosphines. Zhang and co-workers can tune BINAPHANE by modifying EtOH, 100 bar H2 O the groups on the aromatic and/or the phosphine, thus creating a O up to >99% ee general catalytic system useful for obtaining high enantioselectivities in the asymmetric hydrogenation reaction. This ligand demonstrated Scheme 3 excellent enantioselectivity (up to >99% ee) for hydrogenation of E/Z-isomeric mixtures of β-substituted arylenamides (Scheme 6).10 BINAPHANE also proved to be a very good ligand for the palladium O 11 catalyzed enantioselective cyclization of silyloxy-1,6‑enynes. This novel ROR' reaction allows for the synthesis of precursors for naturally occurring NHAc molecules. Using mild conditions and 5 mol% of catalyst, Toste et al. >99% ee reported good yields and good selectivities (Scheme 7).

O R H OCH3 Ar NHAc P H P S NHAc (H C) C C(CH ) >99% ee 3 3 3 3 >99% ee

R O Tosyl HN R'O O OH RR' O OR' R NHAc >99% ee >99% ee >99% ee

Scheme 4

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(R)-BINAPHANE tBu H P

P H P P tBu BINAPINE O O [Rh(NBD)((S)-BINAPINE)]SbF OCH ‑ ‑ OCH3 6 3 (R,R)-1,2 Bis[(R)-4,5 dihydro-3H-binaphtho(1,2-c:2',1'-e)phosphepino] H (20 psi), rt, THF, 24 h Ar NHAc 2 Ar NHAc benzene Up to 10,000 turnovers ‑ ‑ (Z) (S) [253311 88 5] Up to >99% ee C50H36P2 FW 698.77 Scheme 5 650854-100MG 100 mg 650854-500MG 500 mg

(S)-BINAPINE PP (3S,3'S,4S,4'S,11bS,11'bS)-(+)-4,4'-Di-t-butyl- CH 4,4',5,5'-tetrahydro-3,3'-bi-3H-dinaphtho[2,1- H3C 3

ChiralQuest Phosphine CH BINAPHANE 3

Ligands and Complexes c:1',2'-e]phosphepin H P R R [610304‑81‑9] 1 mol % Rh-(R)-BINAPHANE C52H48P2 Ar NHAc P H Ar NHAc H2 (20 psi), rt, CH2Cl2, 24 h FW 734.89 (S) H3C Up to 99.5% ee H3C CH3

Scheme 6 650870-100MG 100 mg 650870-500MG 500 mg

2 OR O 3 (R)-Binaphane-Pd(OH2)2(OTf)2 R (S)-BINAPINE-rhodium complex R1 R1 R3 Et2O / AcOH CH H3C 3 OBn O O O H3C CH3 O Bz P H N - BzN BF4 CH3 Rh+ N

83%, 89% ee 91%, 87% ee 80%, 98% ee 79%, 80% ee P H H3C Scheme 7 H C 3 CH3

[(S)-BINAPINE(cyclooctadiene)rhodium(I)] tetrafluoroborate C60H60BF4P2Rh H FW 1032.78 DuanPhos P H P 659622-100MG 100 mg tBu tBu 659622-500MG 500 mg COOMe COOMe Rh-(S,S,R,R)-DuanPhos H (20 psi), rt, 2 h, MeOH NHAc 2 NHAc TON = 10,000 TOF = 5,000 100% conv, >99% ee

Rh-(S,S,R,R)-DuanPhos OAc OAc MeOH, H2(1.3 atm), rt MeO MeO 96% ee

Scheme 8

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(1R,1′R,2S,2′S)-DuanPhos (R)-C3-TunePhos-ruthenium complex (1R,1′R,2S,2′S)-2,2′-Di-tert-butyl-2,3,2′,3′-tetrahydro- H3C ′ ′ CH3 1H,1H-(1,1 )biisophosphindolyl Cl ‑ ‑ P CH3 Ph [528814 26 8] CH3 Ph H PH CH3 O 2+ C24H32P2 H CH Ru 3 O H3C Complexes and Ligands Phosphine ChiralQuest FW 382.46 P CH3 PH Ph Cl CH3 Ph

[Chloro(R)-C -TunePhos)(p-cymene)ruthenium(II)] chloride 657697-100MG 100 mg 3 C49H46Cl2O2P2Ru 657697-500MG 500 mg FW 900.81 659711-100MG 100 mg (1R,1'R,2S,2'S)-DuanPhos-rhodium complex, 96% 659711-500MG 500 mg ((1R,1'R,2S,2'S)-DuanPhos (cyclooctadiene) rhodium(I)) tetrafluoroborate t-Bu 8 P (S)-Me-f-KetalPhos C32H44BF4P2Rh Rh+ H BF4 H FW 680.35 1,1-Bis[(2S,3S,4S,5S)-2,5-dimethyl-3,4-O-isopropyl- CH P 3 t-Bu idene-3,4-dihydroxyphospholanyl]ferrocene H3C O

C28H40O4P2Fe O CH3 FW 558.41 P 659673-100MG 100 mg H3C 659673-500MG 500 mg Fe H C 3 P (S,S′,R,R′)-TangPhos CH3 O O (1S,1S',2R,2R')-1,1'-Di-tert-butyl-(2,2')-diphospholane H C H 3 CH [470480‑32‑1] 3 P P C16H32P2 H FW 286.37 t-Bu t-Bu 685674-100MG 100 mg S: 22-24/25 (S,S)-f-Binaphane 8 650889-100MG 100 mg 650889-500MG 500 mg

(S,S',R,R')-TangPhos-rhodium complex P Fe

(S,S′,R,R')-TangPhos(cyclooctadiene)rhodium P (I)] tetrafluoroborate t-Bu P C24H44BF4P2Rh Rh+ H BF4 H FW 584.26 P t-Bu 1,1′-Bis[(11bs)-3,5‑dihydro-4H-dinaphtho[2,1‑c:1′,2′-e]phosphenpin-4yl] ferrocene; 1,1′-Bis[(S)-4,5‑dihydro-3H-binaphtho[2,1‑c:1′,2′-e]phosphepino]ferrocene 659703-100MG 100 mg [544461‑38‑3] 659703-500MG 500 mg C54H40P2Fe FW 806.69 (R)-C3-TunePhos 685925-100MG 100 mg (R)-1,13-Bis(diphenylphosphino)-7,8-dihydro-6H-dibenzo [f,h][1,5]dioxonin Chiral Quest Ligands Kit I 8 [301847‑89‑2] O PPh2 O PPh2 Components C39H32O2P2 FW 594.62 (R)-Binaphane (Aldrich 650854) 100 mg (S,S)-f-Binaphane (Aldrich 685925) 100 mg (S)-Binapine (Aldrich 650870) 100 mg 650862-100MG 100 mg (1R,1′R,2S,2′S)-DuanPhos (Aldrich 657697) 100 mg 650862-500MG 500 mg (S)-Me-f-KetalPhos (Aldrich 685674) 100 mg (S,S′,R,R′)-TangPhos (Aldrich 650889) 100 mg (R)-C3-TunePhos (Aldrich 650862) 100 mg 687464-1KT 1 kit

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DSM MonoPhos™ Family

Feringa and co-workers have developed a diverse array of chiral, efficiently hydrogenates a wide range of acetamido derivatives in less monodentate phosphoramidites based on the privileged BINOL time than the corresponding Me-DuPhos analogs.4a Note that the chiral platform.1 The MonoPhos™ family has exhibited high levels of (S,R)-phosphoramidite ligand is the only ligand known to afford greater S MonoPhos DSM enantiocontrol in synthetic transformations ranging from metal-catalyzed than 90% enantioselectivies for the substrate shown (Scheme 3). asymmetric 1,4‑additions of organometallic reagents to allylic alkylations Recently, Feringa's R&D group prepared additional structurally varied to desymmetrization of meso-cycloalkene oxides.2 phosphoramidite ligands for rhodium-catalyzed asymmetric hydrogenations. The aptly named PipPhos and MorfPhos ligands contain Asymmetric 1,4‑Additions piperidinyl and morpholinyl amine subunits, respectively, and are examples of easily synthesized chiral ligands for highly effective of Organometallic Reagents enantioselective transformations. Under mild reaction conditions Feringa and co-workers showcases the high activity of the including low H pressure, this catalyst system yields unprecedented ‑ 2 (S,R,R)-phosphoramidite ligand in copper-catalyzed 1,4 additions of enantioselectivities for several substrates such as dimethyl itaconate and 1 5 organozinc reagents to cyclohexenones. Interestingly, the in situ α-dehydroamino ester derivatives (Scheme 4). ™ formed zinc species originating from the cyclohexenone is readily trapped via a palladium-catalyzed allylation. It was followed by a formal Family annulation process through a palladium-catalyzed Wacker oxidation, and Asymmetric Regioselective Allylic Aminations finally by an aldol cyclization. The high (96%) enantioselectivity of Hartwig and co-workers have succeeded in developing highly selective this methodology is completely retained throughout this synthetic iridium catalysts with the (R,R,R)-phosphoramidite L.2g The allylic strategy (Scheme 1). aminations of a wide variety of achiral allylic esters proceeded with total conversion and superb regioselectivity in many cases. The reaction clearly shows the power of this methodology; wherein, cinnamyl acetate was Highly Asymmetric converted to the allylic benzyl amine in excellent yield and enantiopurity Rhodium-Catalyzed Hydrogenation (Scheme 5). The authors mentioned that these valuable amination Feringa has also gone to great lengths to develop structurally varied reactions were mediated by air-stable Ir complexes at ambient MonoPhos ligands in industrially useful transformations such as temperatures, which should lead to wide acceptance of this catalyst in asymmetric hydrogenation.4 Impressively, the (S)-N-benzyl-N-methyl- bench-top organic synthesis. MonoPhos derivative shown has been utilized in highly selective hydrogenations of (E)-N-acylated dehydro-β-amino acid esters, affording References: (1)(a) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346. (b) Minnaard, A. J. et al. the corresponding enantiopure β-amino acid derivatives (Scheme 2).4a Acc. Chem. Res. 2007, 40, 1267. (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. The authors found that this ligand, after being screened versus related et al. Org. Lett. 2001, 3, 1169. (d) Alexakis, A. et al. Chem. Commun. 2005, 2843. chiral phosphoramidites, afforded the highest enantiocontrol in (e) Streiff, S. et al. Chem. Commun. 2005, 2957. (f) Bertozzi, F. et al. Org. Lett. 2000, 2, hydrogenations, albeit at slightly slower reaction times. 933. (g) Hartwig, J. F. 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, The Feringa research group has broadened the substrate scope of the 308. (5) Bernsmann, H. et al. J. Org. Chem. 2005, 70, 943. asymmetric hydrogenation reaction by generating another chiral center on the amine moiety of the phosphoramidite ligand. Amazingly, this fine ligand tuning produces a very active and productive catalyst, which

O Ph PN O O Ph O CuCl O PdCl2 H 4 mol% (10 mol %) KOtBu O O 1. Cu(OTf)2 (2 mol %) DMF H2O THF, rt o O2 ZnEt2, toluene, 30 C

2. Pd(PPh3)4 (4 mol %) 88%, 96% ee 65%, 96% ee 56%, 96% ee OAc

Scheme 1

Me O O PN cat. PN O O O O NHAc NHAc Ph 4 mol % ∗∗ OMe OMe CO2Et CO2Et HN Rh(cod)2BF4 (2 mol %) HN Rh(cod)2BF4 (2 mol %) 99% ee H2 (10 bar), CH2Cl2, 4 h, rt O H2 (5 bar), CH2Cl2, rt O >99% ee Scheme 2 Scheme 4

O O Ph PN PN NHBn O H O Ph NHAc NH NHAc 2 3 4 mol % Ph CO Me CO2Me 2 (R,R,R)-L*, 2 mol % Ph OAc + + Rh(cod)2BF4 (2 mol %) F [Ir(cod)Cl] (1 mol %), EtOH, rt F H (10 bar), CH Cl , 20 min, rt 2 2 2 2 94% ee Ph NHBn 4 3 equiv Scheme 3 97:3 (3:4), 95%, 95% ee Scheme 5

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(S)-(+)-Benzyl(3,5‑dioxa-4‑phospha-cyclohepta[2,1‑a;3,4‑a′] (R)-(−)-(3,5‑Dioxa-4‑phosphacyclohepta[2,1‑a;3,4‑a′]di-naph- dinaphthalen-4‑yl)methylamine, 97% thalen-4‑yl)dimethylamine, 97% (+)-N-Benzyl-N-methyl-dinaphtho[2,1-d:1′,2′] (R)-Monophos dioxaphosphepin-4-amine, (11bS) [157488‑65‑8] O CH3 O CH3 [490023‑37‑5] PN C22H20NO2P P N O CH C28H22NO2P FW 361.37 O 3 FW 435.45

665355-100MG 100 mg 668206-100MG 100 mg Family 665355-500MG 500 mg 668206-250MG 250 mg ™ 665355-2G 2g 668206-1G 1g 668206-5G 5g (S,R)-(+)-(3,5‑Dioxa-4‑phospha-cyclohepta[2,1‑a;3,4‑a′]dinaphthalen-4‑yl)-(1‑phenylethyl)amine, 96% (S)-(+)-(3,5‑Dioxa-4‑phosphacyclohepta[2,1‑a;3,4- a′]di-naph- ‑ (+)-N-(1(R1-Phenylethyl)-dinaphtho[2,1-d:1′,2′-f] thalen-4 yl)dimethylamine, 97% [1,3,2]dioxaphosphepin-4-amine,.(11b,S) (S)-Monophos [422509‑53‑3] CH [185449‑80‑3] O 3 O CH PNH 3 C28H25NO2P C22H18NO2P P N O FW 438.48 FW 359.36 O CH3 DSM MonoPhos

665347-100MG 100 mg 668192-100MG 100 mg 665347-500MG 500 mg 668192-250MG 250 mg 668192-1G 1g ‑ ‑ ‑ ‑ ′ (S,R,R)-(+)-(3,5 Dioxa-4 phospha-cyclohepta[2,1 a;3,4 a ]di- 668192-5G 5g naphthalen-4‑yl)bis(1‑phenylethyl)amine, 97% (+)-N,N-Bis[(1R)-1-phenylethyl]-dinaphtho[2,1- (11bR)-2,6-Bis(diphenylphosphino)-N,N-dimethyldi- 8 d:1′,2′-f][1,3,2]dioxaphosphepin-4-amine, (11bS) naphtho[2,1-d:1′,2′-f]-1,3,2-dioxaphosphepin-4-amine [415918‑91‑1] O CH3 [913617‑04‑6] C36H30NO2P P N FW 539.60 O CH3 C46H36NO2P3 FW 727.70 P

O CH3 P N 665363-100MG 100 mg O CH3

665363-500MG 500 mg P 665363-2G 2g

(S,S,S)-(+)-(3,5‑Dioxa-4‑phospha-cyclohepta[2,1‑a;3,4‑a']dinaphthalen-4‑yl)bis(1‑phenylethyl)amine, 97% 683248-100MG 100 mg 683248-500MG 500 mg (+)-N,N-Bis[(1S)-1-phenylethyl]- dinaphtho[2,1- d:1′,2′-f][1,3,2]dioxaphosphepin- 4-amine, (11bR) Ph O CH3 [380230‑02‑4] PN O C36H30NO2P CH3 FW 539.60 Ph

665290-100MG 100 mg 665290-500MG 500 mg 665290-2G 2g

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(S)-(+)-(3,5‑Dioxa-4‑phosphacyclohepta[2,1‑a;3,4‑a′]dinaph- (11bS)-N,N-dimethyl-8,9,10,11,12,13,14,15-octahydro- 8 thalen-4‑yl)morpholine, 97% dinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepin-4- amine C24H20NO3P FW 401.39 [389130‑06‑7] O P N O C22H26NO2P

CH MonoPhos DSM O O 3 FW 367.42 P N O CH3

665487-100MG 100 mg 665487-500MG 500 mg 685569-100MG 100 mg 665487-2G 2g 685569-500MG 500 mg

(S)-(+)-(3,5‑Dioxa-4‑phospha-cyclohepta[2,1‑a;3,4‑a′]dinaph- (3aR,8aR)-(−)-(2,2‑Dimethyl-4,4,8,8‑tetraphenyl-tetrahydro- thalen-4‑yl)piperidine, 97% [1,3]dioxolo[4,5‑e][1,3,2]dioxaphosphepin-6‑yl)dimethylamine, 96% ™ (S)-(+)-4-Dinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphos- Family phepin-4-yl-piperidine [213843‑90‑4] O C25H22NO2P PN C33H34NO4P FW 399.42 O FW 539.60 O O CH3 H3C P N H C 3 O O CH3 665479-100MG 100 mg 665479-500MG 500 mg 665479-2G 2g 665460-100MG 100 mg 665460-500MG 500 mg

8 Chiral Vicinal Diamines for Asymmetric Synthesis

Chiral vicinal diamines are of tremendous interest to the synthetic chemist as they are found in many chiral catalysts and pharmaceuticals. Currently, there is no unified approach to making these chiral vicinal diamines, and they are often challenging to synthesize, especially if unsymmetrically substituted. Jik Chin and co-workers have recently reported some preliminary theoretical and experimental studies for converting a parent diamine (1) into other chiral vicinal diamines.1 These diamines can be used as ligands for chiral catalysts, or they can be further elaborated to produce chiral heterocyclic rings and β-lactams via ring closure.

NH OH OH OH OH NH2 OH 2

NH 1 1 2 1) R1CHO N R N R H N R1 [3,3] H2O 2 OH NH OH NH2 2 2) R2CHO NH2 N R2 N R2 2 H2N R 685879 685860 OH OH OH (S,S)-1 (R,R)-1 1

Other 8 Chiral Vicinal Diamines

CH3 OCH3 N O2N H3CO H3C NH2 • 4 HCl NH2 Cl NH2 NH2 OCH3 • 2 HCl • 2 HCl • 2 HCl

NH2 CH3 Cl NH2 NH2 H3CO NH2 N NO2 OCH3 H3CO CH3 685186 684058 684031 684023

H3C

F H3CO CH3 NH NH NH2 2 2 • 2 HCl • 2 HCl NH2 H C CH • 2 HCl 3 3 H2N NH2 NH2 NH2 F OCH3 H3C

CH3 684147 684139 684120 684104

References: (1)(a) Chin, J. et al. J. Am. Chem. Soc. 2003, 125, 15276. (b) Kim, H.-J. et al. J. Am. Chem. Soc. 2005, 127, 16370. (c) Kim, H.-J. et al. J. Am. Chem. Soc. 2005, 127, 16776.

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Reetz Ligands

In 1998, Reetz et al. reported the synthesis of a new generation of ligand (11bS,11′bS)-4,4′-(9,9-Dimethyl-9H-xanthene-4,5-diyl) 8 for enantioselective, catalyzed hydrogenation. Based on BINOL-derived bis-dinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepin diphosphonite molecules, these ligands showed good enantioselectivities for the asymmetric hydrogenation of terminal alkenes, ketones, and S,S-Reetz X-Diphosphonite ‑ ‑ β-keto esters,1,2 and the asymmetric conjugate addition of arylboronic [349114 57 4] 3 C H O P O acid derivatives to α,β-unsaturated carbonyls. 55 36 5 2 P FW 838.82 O

CH3 Enantioselective Hydrogenation of Olefins O CH3 Reetz et al. reported the hydrogenation of two different olefins with O Rh(cod)BF4 and R,R-Reetz F-Diphosphonite. Outstanding yields and P selectivity were reported (Scheme 1).4 O Reetz Ligands

Used with a RuCl2(p-cymene)2 complex, the R,R-Reetz X-Diphosphonite converts a variety of ketones into secondary alcohols with yields and ee's 1 up to 100% and 98%, respectively (Scheme 2). 682869-100MG 100 mg 682869-500MG 500 mg References: (1) Reetz, M. T. et al. J. Am. Chem. Soc. 2006, 128, 1044. (2) Reetz, M. T. et al. Adv. Synth. Catal. 2006, 348, 1157. (3) Reetz, M. T. et al. Org. Lett. 2001, 3, 4083. (4) Reetz, M. T. et al. Chem. Commun. 1998, 2077. (11bR,11′bR)-4,4′-(9,9-Dimethyl-9H-xanthene-4,5-diyl) 8 bis-dinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepin

R,R-Reetz F-diphosphonite R, R-Reetz X-Diphosphonite CO2Me CO2Me ‑ ‑ MeO2C MeO2C [349114 63 2] Rh(cod)BF4, H2 O C55H36O5P2 P 100%, >99.5% ee FW 838.82 O

O O CH3 R,R-Reetz F-diphosphonite O CH3 MeO2CNMe MeO2CNMe H Rh(cod)BF4, H2 H O 100%, >99% ee P O R,R-Reetz F-diphosphonite : O P O Fe O P 682977-100MG 100 mg O 682977-500MG 500 mg

Scheme 1 1,1′Bis[(11bS)-dinaphtho[2,1-d:1′,2′-f][1,3,2] 8 dioxaphosphepin-4-yl]ferrocene

H3CCH3

O O P P P O O O O O Fe O P (1.25 mol%) O O OH [RuCl2(p-cymene)]2 (0.5 mol%) 1 R CH3 R CH3 i PrOH, base (10 mol%) S,S-Reetz F-Diphosphonite R Yield (%) ee (%) ‑ ‑ Ph 93 98 [260395 56 0] m-MeOPh 91 93 C50H32FeO4P2 m-BrPh 100 96 p-ClPh 96 96 FW 814.58 p-BrPh 98 95 682942-100MG 100 mg Scheme 2 682942-500MG 500 mg

1,1′Bis[(11bR)-dinaphtho[2,1-d:1′,2′-f][1,3,2] 8 dioxaphosphepin-4-yl]ferrocene

O P O Fe O P O

R, R-Reetz F-Diphosphonite [217175‑10‑5] C50H32FeO4P2 FW 814.58 L R: 40 S: 23-24/25-36/37 682950-100MG 100 mg

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(11bS,11′bS)-4,4′-(Oxydi-2,1-phenylene)bis-dinaph- 8 (11bR,11′bR)-4,4′-(Oxydi-2,1-phenylene)bis-dinaph- 8 tho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepin tho[2,1-d:, 1′,2′-f][1,3,2]dioxaphosphepin S, S-Reetz D-Diphosphonite R, R-Reetz D-Diphosphonite [898830‑89‑2] [391860‑55‑2] O O C52H32O5P P C52H32O5P P FW 767.78 O FW 767.78 O Ligands Reetz

O O

O O P P O O

JLR: 11-48/20-63-65-67 S: 36/37-46-62 L R: 48/20-63-65 S: 36/37-45-62 682985-100MG 100 mg 682993-100MG 100 mg 682985-500MG 500 mg 682993-500MG 500 mg

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The ChiroSolv Kit Advantage • Ready to use kits — only ® Sigma-Aldrich is pleased to partner with ChiroSolve, Inc. to offer a series of ready-to-use, disposable kits for chiral your racemate is required resolution of both solid and liquid racemates. These kits allow scientists to quickly screen calibrated quantities of resolving agents and solvents against a racemate to ﬁ nd the optimum combination, as well as optimize reaction • Accurate and consistent conditions in order to separate a racemic mixture into its constituent enantiomers. The kits’ high throughput format results allows scientists to identify the optimum resolution process within 24 hours that might otherwise take over 2 months. • Tremendous time and Product Information for Liquid Racemates Product Information for Solid Racemates money savings Prod. No. Prod. Name/Description Prod. No. Prod. Name/Description 681431 ChiroSolv Resolving Kit, Acid Series 1 698881 ChiroSolv Resolving Kit, Acid Series 1 681423 ChiroSolv Resolving Kit, Acid Series 2 699527 ChiroSolv Resolving Kit, Acid Series 2 681415 ChiroSolv Resolving Kit, Acid Series 3 698873 ChiroSolv Resolving Kit, Acid Series 3 699217 ChiroSolv Resolving Kit, Acid Series 4 699225 ChiroSolv Resolving Kit, Acid Series 4 700363 ChiroSolv Resolving Kit, Complete Acid Series 700398 ChiroSolv Resolving Kit, Complete Acid Series 681407 ChiroSolv Resolving Kit, Base Series 1 699233 ChiroSolv Resolving Kit, Base Series 1 For more information, visit 681393 ChiroSolv Resolving Kit, Base Series 2 698938 ChiroSolv Resolving Kit, Base Series 2 sigma-aldrich.com/chirosolv 681377 ChiroSolv Resolving Kit, Base Series 3 698946 ChiroSolv Resolving Kit, Base Series 3 699241 ChiroSolv Resolving Kit, Base Series 4 698954 ChiroSolv Resolving Kit, Base Series 4 ChiroSolv is a registered trademark of 700371 ChiroSolv Resolving Kit, Complete Base Series 700401 ChiroSolv Resolving Kit, Complete Base Series ChiroSolve, Inc.

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BINOL and Derivatives

BINOL and its derivatives are one of the mostly widely used classes of Asymmetric Aldol Reaction ligands in asymmetric synthesis; being utilized in a broad array of reactions including: Diels–Alder, carbonyl addition and reductions, Asymmetric imine aldol reactions are also catalyzed by vaulted Michael additions, as well as many others. While tremendous success has biaryl-derived catalysts, providing an important method for the synthesis of chiral β-amino esters. The addition of silyl ketene acetals to aryl imines been obtained with the BINOL platform, other C2-symmetric diol ligands have attracted considerable attention. Among these are the vaulted in the presence of either Zr-VANOL or Zr-VAPOL catalysts proceeds with biaryl ligands developed by Wulff and co-workers. Both vaulted high asymmetric induction and in excellent yield (Scheme 4, Table 3). Significantly, both catalysts exhibit substantially higher levels of induction 3,3'-biphenanthrol (VAPOL) and vaulted 2,2'-binaphthol (VANOL) have 4 proven to be excellent ligands in catalytic asymmetric Diels–Alder, imine over the analogous BINOL-derived catalyst. aldol, and aziridination reactions (Figure 1).1 Recently the phosphoric acid derivative of VAPOL was shown to be effective as a chiral Brønsted Chiral Brønsted Acid acid catalyst. In many of the examples illustrated herein, the vaulted Antilla and co-workers demonstrated VAPOL hydrogenphosphate to be a biaryls give both higher yields and higher inductions than the same useful chiral Brønsted acid catalyst in the addition of sulfonamides to reactions using a BINOL ligand. Boc-activated aryl imines (Scheme 5).5 The resultant N,N-aminal products were prepared in high yields with impressive enantiopurities. Asymmetric Diels–Alder Reaction The identical reaction with a BINOL-derived Brønsted acid catalyst gave

BINOL and Derivatives an excellent yield (95%), but a dismal level of asymmetric induction Very early on, a catalyst generated from Et2AlCl and VAPOL was shown to be an effective catalyst for the asymmetric Diels-Alder reaction.2 As (<5% ee) was obtained. A variety of sulfonamides and aryl imines are shown in Scheme 1, the cycloaddition of acrolein with cyclopentadiene active in the imine amidation reaction, and the resultant protected in the presence of the VAPOL-derived catalyst gave high conversions and aminals are shelf-stable compounds. excellent stereoselectivities for the exo isomer in very high optical purity. Analogous reactions with the BINOL-derived catalyst provided the References: (1)(a) Bao, J. et al. J. Am. Chem. Soc. 1996, 118, 3392. (b) Zhang, Y. et al. Org. – Lett. 2003, 5, 1813. (c) Yu. S. et al. Org. Lett. 2005, 7, 367. (2)(a) Bao, J.; Wulff, W. D. J. cycloadduct in high yield, but in very low enantiomeric excess (13 41%). Am. Chem. Soc. 1993, 115, 3814. (b) Bao, J.; Wulff, W. D. Tetrahedron Lett. 1995, 36, 3321. (c) Heller, D. P. et al. J. Am. Chem. Soc. 1997, 119, 10551. (3)(a) Antilla, J. C.; Wulff, W. D. J. Am. Chem. Soc. 1991, 121, 5099. (b) Antilla, J. C.; Wulff, W. D. Angew. Chem., Int. Asymmetric Aziridination Reaction Ed. 2000, 39, 4518. (c) Loncaric, C.; Wulff, W. D. Org. Lett. 2001, 3, 3675. (d) Patwardhan, Aziridines are important building blocks in organic synthesis because A. P. et al. Angew. Chem., Int. Ed. 2005, 44, 6169. (e) Patwardhan, A. P. et al. Org. Lett. they allow for convenient access to amines, amino alcohols, diamines, 2005, 7, 2201. (4) Xue, S. et al. Angew. Chem., Int. Ed. 2001, 40, 2271. (5) Rowland, G. B. and other useful nitrogen-containing molecules. Most contemporary et al. J. Am. Chem. Soc. 2005, 127, 15696. methods of chiral aziridine preparation have relied on the chiral pool. Recently, the Wulff group has developed a robust catalytic asymmetric aziridination reaction providing optically active aziridines in high yields and selectivities. The reaction relies on the addition of commercially O available ethyl diazoacetate (EDA) to benzhydryl imines in the presence OH Ph OH Ph OH Ph O 3 P of arylborate catalysts prepared from vaulted aryl ligands and B(OPh)3. OH Ph OH Ph OH Ph O OH The aziridination reaction exhibits excellent selectivities for the cis isomer, and high enantiomeric excesses are obtained. The resultant benzyhydryl- protected aziridines undergo a variety of reactions, including:

deprotection, reductive ring opening, or alkylation reactions (Scheme 2, (S)-BINOL (S)-VANOL (S)-VAPOL (S)-VAPOL Hydrogenphosphate Table 1). The asymmetric synthesis of leukointegrin LFA-1 antagonist BIRT-377 utilized an aziridination/alkylation methodology to provide the Figure 1 hydantoin target in excellent overall yield. The highly expeditious synthesis of the antibacterial agent – CHO ( )-chloramphenicol utilized the asymmetric aziridination reaction, (xs) followed by a nucleophilic ring opening of the aziridine with dichloro- CH3 CHO acetic acid with a subsequent acyl group migration (Scheme 3, Table 2). Et2AlCl/(S)-VAPOL catalyst (1:1) CH3 Both VANOL and VAPOL gave higher yields and stereoselectivities than − (0.5 mol %), CH2Cl2, ca. 80 °C 97% (NMR), 97.7% ee (GC) the BINOL-derived catalyst. Scheme 1

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CHPh N 2 O + N2 (EDA) EtO X IO n Derivatives and BINOL

Ligand/B(OPh)3 catalyst

CHPh2 H Pd black N 1) O3, CH2Cl2, −78 °C NH2 N Ph HCO2H, MeOH, rt CO2Et 2) NaBH4, MeOH CO2Et Ph CO2Et X = H D-phenylalanine X = H 60% ethyl ester, 80% X

LDA, DME/Et2O, −78 °C; then MeI, −78 °C to rt X = 4-Br

CHPh 2 O N H3C CH3 N CO2Et N CH3 O Br Br 86% BIRT−377

Scheme 2

Ligand, Time Yield Time Yield Entry Loading X (h) (%) cis:trans ee (%) Entry Ligand (h) (%) cis:trans ee (%) (S)-BINOL, 1(R)-BINOL 26 72 19:1 22 1 H 3 61 17:1 20 10 mol % 2(S)-VANOL 26 77 >50:1 91a (S)-VANOL, 2 H 0.5 85 >50:1 96 3(R)-VAPOL 21 80 30:1 96 (99% ee recryst.) 10 mol % a Product is the enantiomer of the aziridine shown. (S)-VAPOL, 3 H 48 77 >50:1 95 Table 2 2 mol % (S)-VAPOL, 94 (>99% ee 4 4-Br 20 87 >50:1 1 mol % recryst.) HO Ligand/Zr(Oi-Pr)4 catalyst NH2 O (2.2:1), (2 mol %) Table 1 N + Ph OMe MeO OTMS Ph toluene, 40 °C 100%, 86% ee

CHPh2 Scheme 4 CHPh N 2 N

EtO C Ligand/B(OPh)3 catalyst (10 mol %) 2 O2N toluene, 0 to 22 °C Loading Temp Time Yield ee + NO2 Entry Ligand (mol %) Solvent (°C) (h) (%) (%) EDA Cl2HCCO2H 1(R)-BINOL 20 CH2Cl2 25 4 100 28 1,2-C2H4Cl2, Δ 80% 2(S)-VAPOL 20 Toluene 25 15 94 89 OH OH 3(S)-VAPOL 2 Toluene 40 6 100 86 EtO C HO NaBH4 2 Cl HC NH 2 NO MeOH, 0 °C Cl2HC NH 2 NO2 Table 3 O 74% O (−)-chloramphenicol Boc Boc Scheme 3 NHN (S)-VAPOL Hydrogenphosphate (5 mol %) * + TsNH2 N(H)Ts Et2O, rt, 1 h

95%, 94% ee

Scheme 5

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(R)-(+)-1,1′-Bi(2‑naphthol), 99% (R)-(−)-1,1'-Bi-2‑naphthyl dimethanesulfonate, 97% (R)-BINOL; (+)-2,2′-Dihydroxy-1,1′-dinaphthyl; (R)-(+)-1,1′- [871231‑48‑0] O ′ C H O S CH Binaphthalene-2,2 -diol 22 18 6 2 S 3 OH O [18531‑94‑7] FW 442.50 O OH O C20H14O2 O S CH FW 286.32 O 3

R: 25-36 S: 26-45 RTECS # DU3106100 K L R: 36 S: 26 246948-1G 1g 631795-250MG 250 mg 246948-5G 5g 246948-10G 10 g (S)-(+)-1,1'-Bi-2‑naphthyl dimethanesulfonate, 97% − ′ ‑ [871231‑47‑9] (S)-( )-1,1 -Bi(2 naphthol), 99% O C H O S CH3 22 18 6 2 S O (S)-BINOL; (−)-2,2′-Dihydroxy-1,1′-dinaphthyl; (S)-(−)-1,1′- FW 442.50 O O Binaphthalene-2,2′-diol O S ‑ ‑ OH CH [18531 99 2] O 3 OH C20H14O2 BINOL and Derivatives FW 286.32 L R: 36 S: 26 R: 25-36 S: 26-45 RTECS # DU3106100 K 631787-250MG 250 mg 246956-1G 1g − ‑ 246956-5G 5g (R)-( )-1,1'- Bi-2 naphthyl ditosylate, 98% 246956-25G 25 g [137568‑37‑7] O C H O S O 34 26 6 2 S CH3 − ′ ‑ FW 594.70 O (R)-( )-1,1 -Bi-2 naphthol bis(trifluoromethanesulfonate), O 97% S CH3 O O (R)-1,1′-Binaphthalene-2,2′-diyl bis(trifluoromethanesulfonate); (R)-1,1'-Bi(2-naphthol) bis(trifluorometh- O O R: 36/37/38 S: 26-36 S L anesulfonate) O CF3 O CF [126613‑06‑7] S 3 596914-5G 5g O O C22H12F6O6S2 596914-25G 25 g FW 550.45 M R: 34 S: 26-36/37/39-45 (S)-(+)-1,1'-Bi-2‑naphthyl ditosylate, 97% 440590-250MG 250 mg [128544‑06‑9] O C H O S O 440590-1G 1g 34 26 6 2 S CH3 FW 594.70 O 440590-5G 5g O S CH3 O O (S)-(+)-1,1′-Bi-2‑naphthol bis(trifluoromethanesulfonate), 97% L R: 36/37/38 S: 26-36 (S)-1,1'-Bi(2-naphthol) bis(trifluoromethanesulfonate); 597252-5G 5g (S)-1,1′-Binaphthalene-2,2′-diyl bis(trifluoromethane- O O S 597252-25G 25 g sulfonate) O CF3 O CF [128544‑05‑8] S 3 O O C22H12F6O6S2 FW 550.45 M R: 34 S: 26-36/37/39-45 431893-250MG 250 mg 431893-1G 1g 431893-5G 5g

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(R)-(+)-3,3′-Bis(3,5‑bis(trifluoromethyl)phenyl)-1,1′-bi-2‑naph- (R)-(+)-2,2'-Bis(methoxymethoxy)-1,1'-binaphthalene, 97% thol, 95% [173831‑50‑0] ‑ ‑ C H O [756491 54 0] CF 24 22 4 CH 3 O O 3 C36H18F12O2 FW 374.43 O O FW 710.51 CH3

CF3 Derivatives and BINOL

OH OH LQR: 41-50/53 S: 25-26-36/39-60-61 CF3 631582-250MG 250 mg

CF3 (S)-(−)-2,2'-Bis(methoxymethoxy)-1,1′-binaphthalene, 97% L R: 36/37/38 S: 26 [142128‑92‑5] C H O 24 22 4 CH 674591-100MG 100 mg FW 374.43 O O 3 O O CH3 (S)-(–)-3-3′-Bis(3,5-bis(trifluoromethyl)phenyl)-1,1′-bi- 8 2-naphthol, 95% R: 41-50/53 S: 25-26-36/39-60-61 (1S)-3,3′-Bis[3,5-bis(trifluoromethyl)phenyl]1,1′-bi- LQ CF3 naphthalene-2,2′-diol 631574-250MG 250 mg [849939‑13‑5] CF3 C36H18F12O2 (R)-3,3′-Bis(triphenylsilyl)-1,1′-bi-2‑naphthol, 96% FW 710.51 OH OH ′ ′ ′ (R)-3,3 -Bis(triphenylsilyl)-1,1 -binaphthalene-2,2 -diol Ph Ph CF [111822‑69‑6] Si 3 Ph C56H42O2Si2 FW 803.10 OH CF3 OH

Ph Si R: 36 S: 26 Ph L Ph 681539-100MG 100 mg 674737-100MG 100 mg (R)-(−)-3,3′-Bis(3,5‑dimethylphenyl)-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-bi-2‑naphthol, 97% (S)-(–)-3,3′-Bis(triphenylsilyl)-1,1′-bi-2‑naphthol, 96% C H O Si (R)-3,3′-Bis(3,5-dimethylphenyl)-5,6,7,8,5,′,6′,7′,8′- 56 42 2 2 Ph CH3 Ph ′ ′ FW 803.10 Si octahydro-[1,1 ]binaphthalenyl-2, 2 -diol Ph C36H38O2 OH FW 502.69 CH3 OH OH Ph OH Si Ph Ph CH3

680206-100MG 100 mg CH3 (R)-(+)-3,3′-Dibromo-1,1′-bi-2‑naphthol, 97% 669180-100MG 100 mg ‑ ‑ [111795 43 8] Br (S)-(+)-3,3′-Bis-(3,5‑dimethylphenyl)-5,5′,6,6′,7,7′,8,8′-octa- C20H12Br2O2 hydro-1,1′-bi-2‑naphthol, 97% FW 444.12 OH OH (S)-3,3′-bis-(3,5-dimethylphenyl)-5,6,7,8,5′,6′,7′,8′- CH3 octahydro-[1,1′]binaphthalenyl-2,2′-diol Br C36H38O2 FW 502.69 CH3 595721-250MG 250 mg OH 595721-1G 1g OH

CH3

669172-100MG 100 mg

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(R)-(−)-6,6′-Dibromo-1,1′-bi-2‑naphthol, 98% (R)-(+)-3,3′-Dibromo-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-bi-2,2′- ‑ ‑ naphthalenediol, 97% [65283 60 5] Br ‑ ‑ C20H12Br2O2 [65355 08 0] Br FW 444.12 OH C20H20Br2O2 OH FW 452.18 OH OH Br Br L R: 36/37/38 S: 26-36 L R: 36/37/38 S: 26-36 482617-500MG 500 mg 540587-100MG 100 mg (S)-(+)-6,6′-Dibromo-1,1′-bi-2‑naphthol, 98% 540587-1G 1g [80655‑81‑8] Br (S)-(−)-3,3′-Dibromo-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-bi-2,2′- C20H12Br2O2 FW 444.12 OH naphthalenediol, 97% OH ‑ ‑ [765278 73 7] Br Br C20H20Br2O2 FW 452.18 OH BINOL and Derivatives L R: 36/37/38 S: 26-36 OH Br 482625-250MG 250 mg 482625-500MG 500 mg L R: 36/37/38 S: 26-36 (S)-(−)-3,3′-Dibromo-1,1′-bi-2‑naphthol, 96% 540595-100MG 100 mg 540595-1G 1g ‑ ‑ [119707 74 3] Br C H Br O 20 12 2 2 (R)-(+)-2,2′-Dimethoxy-1,1′-binaphthalene, 97% FW 444.12 OH OH (R)-(+)-2,2′-Dimethoxy-1,1′-binaphthyl; (R)-1,1′-Bi-2-

Br naphthyl dimethyl ether [35294‑28‑1] OCH3 OCH3 C22H18O2 595837-250MG 250 mg FW 314.38 595837-1G 1g L R: 41 S: 26-36 (R)-(+)-6,6'-Dibromo-2,2′-bis(methoxymethoxy)-1,1′-binaphthalene, 97% 595403-250MG 250 mg [179866‑74‑1] Br (S)-(−)-2,2'-Dimethoxy-1,1'-binaphthalene, 97% C24H20Br2O4 CH FW 532.22 O O 3 (S)-(−)-2,2'-Dimethoxy-1,1'-binaphthyl; (S)-1,1′-Bi-2- O O CH3 naphthyl dimethyl ether ‑ ‑ OCH3 Br [75640 87 8] OCH3 C22H18O2 L R: 41 S: 25-26-36/39 FW 314.38 631604-250MG 250 mg L R: 41 S: 26-36 595519-250MG 250 mg (S)-(−)-6,6'-Dibromo-2,2′-bis(methoxymethoxy)-1,1′-binaphthalene, 97% (R)-(+)-Dimethyl-2,2′-dihydroxy-1,1′-binaphthalene-3,3′- ‑ ‑ [211560 97 3] Br dicarboxylate, 98% C24H20Br2O4 CH ‑ ‑ FW 532.22 O O 3 [18531 91 4] O O O C24H18O6 OCH CH3 FW 402.40 3 Br OH OH R: 41 S: 25-26-36/39 L OCH3 O 631590-250MG 250 mg L R: 36/37/38 S: 26-36 579343-2G 2g

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(S)-(−)-Dimethyl-2,2′-dihydroxy-1,1′-binaphthalene-3,3′- (S)-VANOL, 97% dicarboxylate (S)-3,3′-Diphenyl-2,2′-bi(1-naphthalol); (S)-3,3′-Diphenyl- ‑ ‑ ′ [69678 00 8] O 2,2 -bi-(1-naphthol) C24H18O6 [147702‑14‑5] OCH3 FW 402.40 C32H22O2 Ph OH OH FW 438.52 Ph OH Derivatives and BINOL OH

OCH3

O R: 37/38-41 S: 26-36/37/39 L R: 36/37/38 S: 26-36 L 676098-250MG 250 mg  98% 579971-2G 2g (R)-VAPOL, 97% (R)-(+)-5,5′,6,6′,7,7′,8,8′-Octahydro-1,1′-2‑naphthol (R)-2,2'-Diphenyl-3,3'-(4-biphenanthrol); (R)-2,2'- Diphenyl-3,3'-(4-biphenanthrol) [65355‑14‑8] [147702‑16‑7] C H O 20 22 2 C40H26O2 Ph OH FW 294.39 OH FW 538.63 Ph OH OH

R: 36/37/38 S: 26-36 L L R: 37/38-40-41 S: 26-36/37/39  97% 675210-100MG 100 mg 540560-1G 1g 675210-250MG 250 mg  95% 675210-500MG 500 mg 569917-1G 1g 569917-5G 5g (S)-VAPOL, 97% (S)-2,2'-Diphenyl-(4-biphenanthrol); (S)-2,2'-Diphenyl-(4- (S)-(−)-5,5′,6,6′,7,7′,8,8′-Octahydro-1,1′−bi-2‑naphthol, 97% biphenanthrol) ‑ ‑ [65355‑00‑2] [147702 15 6] C40H26O2 Ph OH C20H22O2 Ph OH FW 294.39 OH FW 538.63 OH

L R: 36/37/38 S: 26 L R: 37/38-40-41 S: 26-36/37/39 540579-100MG 100 mg 675334-100MG 100 mg 540579-1G 1g 675334-250MG 250 mg 675334-500MG 500 mg (R)-VANOL, 97% (R)-3,3'-Diphenyl-2,2'-bi-1-naphthalol; (R)-3,3'-Diphenyl- BINOL Ligands Kit I 2,2'-bi-1-naphthol [147702‑13‑4] C32H22O2 Ph OH FW 438.52 Ph OH

L R: 37/38-41 S: 26-39 675156-250MG 250 mg

Components (S)-(−)-1,1′-Bi(2‑naphthol) (Aldrich 246956) 1g (S)-(+)-6,6′-Dibromo-1,1′-bi-2‑naphthol (Aldrich 482625) 250mg (S)-(−)-5,5′,6,6′,7,7′,8,8′-Octahydro-1,1′−bi-2‑naphthol (Aldrich 540579) 100mg (S)-(−)-3,3′-Dibromo-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-bi-2,2′-naphthalenediol (Al- drich 540595) 100mg (S)-(−)-2,2'-Dimethoxy-1,1'-binaphthalene (Aldrich 595519) 250mg (S)-(−)-3,3′-Dibromo-1,1′-bi-2‑naphthol (Aldrich 595837) 250mg K R: 25-37/38-41 S: 26-39-45 669113-1KT 1 kit

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TADDOL

Ar Ar The chiral auxiliaries TADDOLs (α,α,α,α-tetraaryl-1,3-dioxolane-4,5- H O R O Oi-Pr dimethanols) developed by Seebach's group have found numerous Ti R O O Oi-Pr applications in asymmetric synthesis ranging from utilization as H stoichiometric chiral reagents or in Lewis acid mediated reactions, to Ar Ar roles in catalytic hydrogenation and stereoregular metathesis (i-PrO)2Ti-TADDOLate (0.05-0.2 eq) 1 polymerization. Et Zn (1-2 eq.) O 2 OH Ti(Oi-Pr)4 (1-2 eq.) CH H 3 -75° to 0°C TADDOL Nucleophilic Addition The principal field of application of TADDOLs to date is in Ti-catalyzed, 98% ee enantioselective reactions. Nucleophilic additions of organometallic

compounds to aldehydes are depicted in Scheme 1. The preparation of OH HO OH OH the Ti-TADDOLate complex used in such transformations is critical with CH3 1 CH3 respect to reproducibility. H C CH 3 3 TMS Enantioselective transfers of allyl groups to aldehydes are most successful 98% ee 99% ee 96% ee using Duthaler's CpTi-TADDOLate complexes 449520 or 449539 2 O (Scheme 2). OH OH CH2 CH3 CH H3C 3 TBSO Enantioselective Transesterification O2N H OH Several examples of enantioselective transesterifications were reported 96% ee 98% ee 99% de for ring openings of lactones and cyclic anhydrides using Ti-TADDOLate of 393762 (Scheme 3). The observed selectivity in this desymmetrization Scheme 1 step is largely independent of structure. The half esters obtained are readily converted into the corresponding γ-lactones.3

It is worth mentioning that TADDOL 395242 bearing 1‑naphthyl groups Ph Ph H O infrequently differs in its reactivity from the other TADDOLs (a dramatic H C O 3 Ti loss in enantioselectivity is observed in Ti-TADDOLate catalyzed addition H C 3 O O Cl H OH reactions described previously). This change in reactivity could be Ph Ph MR1 2 explained with the higher steric hindrance around the chiral pocket of 2 R CH2 4 R -CHO R1 the active site. M = Li, MgCl, MgBr

Enantioselective Protonation OH Nevertheless, surprisingly stereoselective examples using TADDOL OH OH CH2 395242 were found in enantioselective protonation reactions CH C H CH 5 2 9 19 2 (Scheme 4), the first example of a catalytic enantioselective fluorination CH3 CH3 reaction reported by Hintermann and Togni used the Cl2Ti-complex of 6 395242 (Scheme 5) as well as the recent example reported by Rawal 98% ee, 98% de 98% ee, >98% de 98% ee, >98% de using 395242 as a Brønsted acid organocatalyst in a highly 7 OH enantioselective hetero-Diels-Alder reaction (Scheme 6). OH OH OH OH N CH2 H2C OTrt H2C OTrt References: (1) Seebach, D.; Beck, A. K.; Heckel, A. Angew. Chem., Int. Ed. 2001, 40, O TMS 92‑138. (2) Duthaler, R. O.; Hafner, A. Chem. Rev. 1992, 92, 807‑832. (3)(a) Seebach, D.; 85%, 94% de 75%, 94% de 94% ee, 98% de Jaeschke, G.; Wang, Y. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 2395‑2396. (b) Jaeschke, G.; Seebach, D. J. Org. Chem. 1998, 63, 1190‑1197. (4)(a) Seebach, D.; Dahinden, R.; Marti, R. E.; Beck, A. K.; Plattner, D. A.; Kühnle, F. N. M. J. Org. Chem. 1995, 60, Scheme 2 1788‑1799. (b) Seebach, D.; Dahinden, R.; Marti, R. E.; Beck, A. K.; Plattner, D. A.; Kühnle, F. N. M. J. Org. Chem. 1995, 60, 5364. (5) Cuenca, A.; Medio-Simón, M.; Asensio Aguilar, G.; Weibel, D.; Beck, A. K.; Seebach, D. Helv. Chim. Acta 2000, 83, 3153‑3162. (6) Hintermann, L.; Togni, A. Angew. Chem., Int. Ed. 2000, 39, 4359‑4362. (7) Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H. Nature 2003, 424, 146.

H O H O H O 1.2 eq.(Oi-Pr)2TiTADDOLate Oi-Pr H2O Oi-Pr O THF, 5-6d, - 15 °C OTi(Oi-Pr)TADDOLate OH H O H O H O

CO2i-Pr CO2i-Pr H3CCO2i-Pr H3C CO i-Pr H3C 2 H C CO H CO2H CO2H 3 2 CO2H 96% ee 96% ee >90% ee 98% ee

Scheme 3

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Ar Ar Ar Ar O OH O OH H3C H3C H3C O OH H3C O OH Ar Ar Ar Ar Ar = 1-Naphthyl O Ar = 1-Naphthyl O 3 eq. 0.05 eq. O O i-Pr OO i-Pr CH3 MeLi•LiBr (1.2 eq) CH3 Selectfluor® H C H C TADDOL 3 O 3 O CH2Cl2/Et2O CH3 CH3CN F CH3 -78 °C to -35 °C 75%, 98% ee i-Pr i-Pr i-Pr i-Pr 88%, 90% ee Scheme 4 Scheme 5

Ar Ar O OH H3C H C H C CH 3 O OH H CCH 3 N 3 3 N 3 Ar Ar CH COCl O 3 Ar = 1-Naphthyl O CH2Cl2/toluene O + HPh toluene -78°, 15 min TBDMSO TBDMSO Ph OPh

70%, 99% ee Scheme 6

(4R,5R)-2,2‑Dimethyl-α,α,α′,α′-tetraphenyldioxolane- Chlorocyclopentadienyl[(4S,5S)-2,2‑dimethyl-α,α,α′,α′-tetra- 4,5‑dimethanol phenyl-1,3‑dioxolane-4,5‑dimethanolato]titanium, 97%

(−)-2,3-O-Isopropylidene-1,1,4,4-tetraphenyl-L- (4S,5S)-Chloro-cyclopentadienyl-[2,2-dimethyl-1,3- threitol; (−)-trans-α,α′-(2,2-Dimethyl-1,3-dioxolane- OH HO dioxolan-4,5-bis(diphenylmethoxy)]titanium; (S,S)- 4,5-diyl)bis(diphenylmethanol); TADDOL; 1,1,4,4- Duthaler-Hafner reagent; [(4S,5S)-2,2-Dimethyl-1,3- O O H3C Cl Tetraphenyl-2,3-O-isopropylidene-L-threitol; (4R,5R)- O O dioxolan-4,5-bis(diphenylmethoxy)]cyclopentadienyl- Ti 4,5-Bis(diphenylhydroxymethyl)-2,2-dimethyl- chlorotitanium H3C O O H3CCH3 dioxolane [140462‑73‑3] [93379‑48‑7] C36H33ClO4Ti C31H30O4 FW 612.96 FW 466.57 M R: 34 S: 26-36/37/39-45 265004-250MG 250 mg 449539-500MG 500 mg 265004-1G 1g (4R,5R)-2,2‑Dimethyl-α,α,α′,α′-tetra(2‑naphthyl)dioxolane- 4,5‑dimethanol, 99% (4S,5S)-2,2‑Dimethyl-α,α,α′,α′-tetraphenyldioxolane- 4,5‑dimethanol, 97% (−)-DINOL; (−)-2,3-O-Isopropylidene-1,1,4,4- tetra(2-naphthyl)-L-threitol (+)-2,3-O-Isopropylidene-1,1,4,4-tetraphenyl-D- [137365‑09‑4] threitol; (4S,5S)-4,5-Bis(diphenylhydroxymethyl)-2,2- OH HO C47H38O4 HO OH dimethyldioxolane; (+)-trans-α,α′-(2,2-Dimethyl-1,3- FW 666.80 dioxolane-4,5-diyl)bis(diphenylmethanol) O O ‑ ‑ OO [93379 49 8] H3CCH3 H CCH C31H30O4 3 3 FW 466.57 393754-1G 1g 264997-250MG 250 mg 264997-1G 1g (4S-trans)-2,2‑Dimethyl-α,α,α′,α′-tetra(2‑naphthyl)-1,3‑dioxolane-4,5‑dimethanol, 98% Chlorocyclopentadienyl[(4R,5R)-2,2‑dimethyl-α,α,α′,α′-tetra- (4S,5S)-2,2-Dimethyl-α,α,α′,α′-tetra(2- phenyl-1,3‑dioxolane-4,5‑dimethanolato]titanium, 97% naphthyl)dioxolane-4,5-dimethanol; (+)- (4R,5R)-Chloro-cyclopentadienyl-[2,2-dimethyl-1,3- DINOL; (+)-2,3-O-Isopropylidene-1,1,4,4-tetra dioxolan-4,5-bis(diphenylmethoxy)]titanium; (R,R)- (2-naphthyl)-D-threitol HO OH [137365‑16‑3] Duthaler-Hafner reagent; [(4R,5R)-2,2-Dimethyl-1,3- O O H3C Cl O O Ti C47H38O4 dioxolan-4,5-bis(diphenylmethoxy)]cyclopenta- H C 3 O O FW 666.80 dienyl-chlorotitanium H3CCH3 [132068‑98‑5] 393762-250MG 250 mg C36H33ClO4Ti FW 612.96 393762-1G 1g M R: 34 S: 26-36/37/39-45 (4S-trans)-2,2‑Dimethyl-α,α,α′,α′-tetra(1‑naphthyl)-1,3‑diox- 449520-100MG 100 mg olane-4,5‑dimethanol, 99% 449520-500MG 500 mg [171086‑52‑5] C47H38O4 FW 666.80 HO OH

O O

H3CCH3

395242-1G 1g

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BOX

C -symmetric chiral bisoxazolines (BOX) are privileged structures because H3CCH3 2 OO they promote a great number of transformations with unprecedented NN selectivity.1 In 1991, in the same Journal of American Chemistry issue, Cu two communications appeared by Evans2 and Corey.3 These two Ph OTf Ph Ts publications have paved the way for a rapidly and ever-growing number 5 mol% Ar H PhI=NTs Ar N of examples where BOX ligands are used successfully as chiral ligands. H

BOX H R 24 h, r.t. H R Evans described the cyclopropanation of alkenes using diazo esters up to 97% ee catalyzed by a complex formed of 406147 and Cu(I)OTf. With the ester derived from 2,6‑di-tert-butyl-4‑methylphenol (BHT) it was Scheme 2 found that the increased steric demand displays increased trans selectivity (Scheme 1).2 In a related experiment, Evans announced the first catalytic H3CCH3 OO enantioselective aziridination of styrene.4 Two years later, he reported NN on an extension of this preliminary work in a full communication Cu i-Pr TfO OTf i-Pr (Scheme 2). Using BOX ligand 405000, complexed to Cu(I)OTf, in the O (0.66 mol%) O H catalytic enantioselective aziridination of styrene, the BOX ligand having PhNHNH2 (0.70 mol%) O Ethyl diazoacetate (2.67 eq.) 3C OH phenyl substituents proved to be superior to the one bearing sterically OCH3 OCH3 O CH Cl H O demanding t-Bu groups (Scheme 2). O 2 2 O R CHO Recently, Reiser et al. discovered a general route to disubstituted 85-90% ee γ -butyrolactones. In an Cu(I)-catalyzed asymmetric cyclopropanation of Scheme 3 furans with diazo esters, bis(4‑isopropyloxazoline) 680192 was used as chiral ligand (Scheme 3). This transformation was carried out on 50–100 g scale without a detectable loss of enantioselectivity.5 H3CCH3 In his 1991 Journal of American Chemical Society communication, OO Corey used BOX ligand 405000 in an Fe(III)-catalyzed enantioselective NN 3 Fe Diels–Alder reaction (Scheme 4). Ph Cl Cl Ph 10 mol% I (0.5 eq.) Two year later, Evans described the Cu(II)-catalyzed version of the O O 2 H O enantioselective Diels–Alder reaction of unsubstituted acrylimides cyclopentadiene (3 eq.) 6 NO O N O using BOX ligand 406147 as a chiral Lewis acid. The reaction proceeded -50°, 1 h, CH2Cl2

in good yield exhibiting excellent enantioselectivity for the endo 85% diastereoisomer (Scheme 5). From further investigations by Evans et al., endo:exo 97:3 it appears that the best combination is BOX 406147 and Cu(II), and the 90:10 er (endo) 1 best counterions are OTf and SbF6. Scheme 4 4‑Aryl- and 4‑alkylsubstituted BOX-based catalysts were widely used in a large number of reactions1 and their behavior can provide a good representation of their efficiency. But BOX ligands with other structural H3CCH3 motifs have been successfully used too. BOX ligand 405981 has been OO used in the Cu(I)-catalyzed highly enantioselective Mannich reactions to N N ‑ Cu efficiently produce highly functionalized 4 oxo-glutamic ester derivatives R 7 t-Bu TfO OTf t-Bu (Scheme 6). 10 mol% O O O cyclopentadiene Recently, Ma et al. reported on the enantioselective CuI/bis(oxazoline)- NO NO R O catalyzed addition of propiolates and terminal ynones to CH2Cl2 1‑acylpyridinium salt to afford highly functionalized dihydropyridines endo:exo = 95:5 with excellent enantioselectivity using 464155 (Scheme 7).8 It is found up to 98%ee that the carbonyl group adjacent to the alkyne moiety is essential for the enantioselectivity of the addition. Scheme 5

References: (1)(a) Desimoni, G.; Faita, G.; Jørgensen, K. A. Chem. Rev. 2006, 106, 3561‑3651. (b) Ghosh, A. K.; Mathivanan, P., Cappiello, J. Tetrahedron: Asymmetry 1998, O O ‑ ‑ Ph Ph 9,145. (c) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325 335. (2) Evans, D. A.; NN Woerpel, K. A.; Hinman, M. M.; Faul, M. M. J. Am. Chem. Soc. 1991, 113, 726. (3) Corey E. Cu Ph TfO OTf Ph J.; Imai, N.; Zhang, H.-Y. J. Am. Chem. Soc. 1991, 113, 728. (4) Evans, D. A.; Faul, M. M.; Tos Tos O O HN Bilodeau, M. T.; Anderson, B. A.; Barnes, D. M. J. Am. Chem. Soc. 1993, 115, 5328‑5329. N 10 mol% ‑ R + (5)(a) Jezek, E.; Schall, A.; Kreitmeier, P.; Reiser, O. Synlett 2005, 915 918. (b) Chhor, R. B.; EtO C EtO C H EtO2C CO2Et 2 2 CH Cl , r.t. to 40 °C, 20-40 h Nosse, B.; Sörgel, S.; Böhm, C.; Seitz, M.; Reiser, O. Chem. -Eur. J. 2003, 9, 260‑270. 2 2 R ‑ (6) Evans, D. A.; Miller, S. J.; Lecta, T. J. Am. Chem. Soc. 1993, 115, 6460 6461. (7) Juhl, K.; 70-98%, 78-98% ee Gathergood, N.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2001, 40, 2995. (8) Sun, Z.; Yu, ‑ S.; Ding, Z; Ma, D. J. Am. Chem. Soc. 2007, 129, 9300 9301. Scheme 6

H3CCH3 OO OO NN Cu N N t-Bu OTf t-Bu Cu BHTO 1 mol % LiAlH4 I + R R R N2 OH O CHCl3, r.t. CO2BHT 10 mol% R = Ph: trans:cis 150:1; >99% ee + HC R N I N R R = Bn: trans: cis 84:1; >99% ee i-Pr2NPr, CH2Cl2, -78° CO2CH3 CO2CH3 Scheme 1 up to 99% ee Scheme 7

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2,2‑Bis((4S)-(–)-4‑isopropyloxazoline)propane, 96% 2,2′-Methylenebis[(4S)-4‑phenyl-2‑oxazoline], 97% S-4,5-Dihydro-2-(2-((S)-4,5-dihydro-4-isopropyl- (S,S)-2,2′-Methylenebis(4-phenyl-2-oxazoline) CH3 CH3 oxazol-2-yl)propan-2-yl)-4-isopropyloxazole [132098‑59‑0] H3C N N CH3 N N C15H26N2O2 C19H18N2O2 FW 266.38 O O FW 306.36 O O

H3C CH3 BOX R: 36/37/38 S: 26-36 Fp: 110 °C (230 °F) L R: 36 S: 26 Fp: 230 °F L 416428-250MG 250 mg 680192-500MG 500 mg 416428-1G 1g 2,2'-Isopropylidenebis[(4S)-4-tert-butyl-2‑oxazoline], 99% 2,2′-Bis[(4S)-4‑benzyl-2‑oxazoline], 98% (S,S)-2,2′-Isopropylidene-bis(4-tert-butyl-2- CH CH3 ′ H C 3 (S,S)-2,2'-Bis(4-benzyl-2-oxazoline); (S,S)-4,4 - oxazoline) 3 CH3 N H C N N Dibenzyl-2,2′-bi(2-oxazoline) N [131833‑93‑7] 3 CH3 [133463‑88‑4] O C17H30N2O2 O O O FW 294.43 H3C CH3 C20H20N2O2 FW 320.39 L R: 36/37/38 S: 26-36 L R: 36/37/38 S: 26-36 406147-50MG 50 mg 405973-250MG 250 mg 406147-250MG 250 mg 405973-1G 1g ′ ‑ 2,2 -Methylenebis[(4S)-4-tert-butyl-2 oxazoline], 99% 2,2′-Methylenebis[(4R,5S)-4,5‑diphenyl-2‑oxazoline], 99% ′ (S,S)-2,2 -Methylenebis(4-tert-butyl-2-oxazoline) CH ′ ′ ′ CH3 3 (4R,5S,4 R,5 S)-2,2 -Methylenebis(4,5-diphenyl- ‑ ‑ H3C [132098 54 5] CH3 2-oxazoline) H3C N N CH C15H26N2O2 3 [139021‑82‑2] N N FW 266.38 O O C31H26N2O2 O O FW 458.55 L R: 36/37/38 S: 26-36 R: 36/37/38 S: 26-36 405965-500MG 500 mg L 405981-250MG 250 mg ′ ‑ ‑ (+)-2,2 -Isopropylidenebis[(4R)-4 phenyl-2 oxazoline], 97% 405981-1G 1g (R,R)-2,2'-Bis(4-phenyl-2-oxazolin-2-yl)propane; (R,R)-2,2′-Isopropylidenebis(4-phenyl-2- (4S)-(+)-4-[4-(tert-butyl)phenyl]-α-[(4S)-4-[4-(tert-bu- 8 oxazoline) N N tyl)phenyl]-2-oxazolidinylidene]-2-oxazolineaceto- [150529‑93‑4] O O nitrile, 97% H C CH C21H22N2O2 3 3 CH FW 334.41 CH3 3 H C 3 CH3 R: 23/24/25 S: 26-36-45 H C K 3 CH3 406961-250MG 250 mg N HN 406961-1G 1g O O CN

(−)-2,2′-Isopropylidenebis[(4S)-4‑phenyl-2‑oxazoline], 97% Bis[(4S)-4-(4-tert-butylphenyl)-4,5‑dihydro-2‑oxazolyl]acetonitrile C H N O (S,S)-2,2′-Isopropylidenebis(4-phenyl-2- 28 33 3 2 FW 443.58 oxazoline); (S,S)-2,2-Bis(4-phenyl-2-oxazolin-2-yl) R: 36/37/38 S: 26 propane N N L ‑ ‑ O O [131457 46 0] 682772-250MG 250 mg H3C CH3 C21H22N2O2 FW 334.41 − ‑ ‑ S: 22-24/25 Fp: 110 °C (230 °F) (4S,4'S)-( )-2,2'-(3 Pentylidene)bis(4 isopropyloxazoline), 97% 405000-250MG 250 mg 405000-1G 1g (4S,4'S)-(−)-2,2'-(1-Ethylpropylidene)bis(4,5- dihydro-4-isopropyloxazole); [S-(R*,R*)]-(−)-2,2'- N HN (+)-2,2'-Isopropylidenebis[(4R)-4‑benzyl-2‑oxazoline], 98% (1-Ethylpropylidene)bis(4,5-dihydro-4-isopropyloxazole) O O [R(R*,R*)]-(+)-2,2′-Isopropylidenebis(4- ‑ ‑ CN N N [160191 65 1] benzyl-2-oxazoline); (R,R)-(+)-2,2'-Isopropyl- C17H30N2O2 idenebis(4-benzyl-2-oxazoline) O O FW 294.43 H3C CH3 [141362‑77‑8] L R: 36/37/38 S: 26-36 Fp: 82 °C (180 °F) C23H26N2O2 FW 362.46 650897-500MG 500 mg L R: 36/37/38 S: 26-36 650897-1G 1g 495301-250MG 250 mg 495301-1G 1g

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(4S)-(+)-Phenyl-α-[(4S)-phenyloxazolidin-2‑ylidene]-2‑oxazol- [3aR-[2(3′aR*,8′aS*),3′aβ,8′aβ]]-(+)-2,2′-Methylenebis[3a,8a- ine-2‑acetonitrile, 97% dihydro-8H-indeno[1,2-]oxazole], 98% (S,S)-4-Phenyl-α-(4-phenyloxazolidin-2-ylidene)-2- [180186‑94‑1] oxazoline-2-acetonitrile C21H18N2O2 N N [150639‑33‑1] NH N FW 330.38 C20H17N3O2 O O O O FW 331.37 CN R: 36/37/38 S: 26-36 BOX L R: 36/37/38 S: 26-36 L 464155-500MG 500 mg 417068-250MG 250 mg 417068-1G 1g (1S,9S)-1,9‑Bis[(tert-butyldimethylsiloxy)methyl]-5‑cyanose- micorrin, ≥97.0% (HPLC) ′ ′ ′ α ′ α − ′ [3aS-[2(3 aR*,8 aS*),3 a ,8 a ]]-( )-2,2 -Methylenebis[3a,8a- Semicorrin chiral ligand 2 CN dihydro-8H-indeno[1,2-d]oxazole], 98% [105251‑52‑3] C H N O Si [175166‑49‑1] 24 45 3 2 2 HNN FW 463.80 C21H18N2O2 OO FW 330.38 N N H3C CH3 Si CH3 H3C Si H3C CH3 CH H C O O H3C 3 3 CH3 L R: 36/37/38 S: 26-36 L R: 36/37/38 S: 26-36 467073-100MG 100 mg 14556-10MG 10 mg 467073-500MG 500 mg

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Asymmetric Synthesis

Z273694 Z282626 Z370029 Z511811 Z557544 Chiral Auxiliaries Advanced Asymmetric Principles and Asymmetric Catalysis and Ligands in Asymmetric Synthetic Applications of on Industrial Scale: Asymmetric Synthesis Synthesis Methodology Asymmetric synthesis Challenges, Approaches and Solutions

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PYBOX

The PYBOX ligand,1 consisting of a pyridine ring flanked by two 2 oxazoline groups, was introduced in 1989 by Nishiyama. PYBOX evolved O N O directly from the BOX ligands. In comparing them, two points merit to be NNCu OTf PYBOX Ar2 Ph Ph Ar2 mentioned: (1) the binding site of PYBOXes is big enough to complex N 10 mol% HN even lanthanide cations and (2) the rigidity of the tridentate PYBOX + Ph H ** Ar1 H Ar1 scaffold is increased. H2O or toluene Ph In his very first application, Nishiyama showed that isopropyl-PYBOX 78-96% ee 407151 rhodium(III) catalyst effectively promotes the asymmetric hydrosilylation of ketones giving extremely high enantioselectivities Scheme 2 (Scheme 1).3 Li and Wei reported in 2002 the copper(I)-catalyzed enantioselective direct-addition of terminal alkynes to imines. The most successful ligand tested was PYBOX 496073 bearing phenyl groups (Scheme 2).4 O N O N La N Recently, Shibasaki's group reported on lanthanum aryl oxide/PYBOX- ArO OAr S i-Pr OAr i-Pr S catalyzed direct asymmetric Mannich-type reactions using a O O 5 S 10 mol% S trichloromethyl ketone as a propionate equivalent donor. The N O O LiOAr (0.5 mol%) O NH O + H C La(OAr)3-i-Pr-PYBOX 407151 + LiOAr system gave products in 3 R CCl ‑ R H CCl3 THF/toluene (1:1, 1M) 3 72 to >99% yield, 8:1 to >30:1 dr, and 92 98% ee (Table 1). MS 3Å, -40° CH3 The chiral indium(III)-PYBOX complex prepared from indium triflate and (Ar = 4-CH3O-C6H4-) C2-symmetric chiral PYBOX 673986 was found to be an effective chiral Entry R % Yield dr (syn:anti) % ee (syn) ligand for the enantioselective allylation reaction of aldehydes with allyltributylstannane, giving high enantioselectivities.6 Using this 1 Ph 96 21:1 96 methodology, the chiral steroidal aldehyde could be allylated with 2 4-Cl-C H 97 20:1 96 excellent enantioselectivity ((22S):(22R)= >99:1) and in good yield (78%). 6 4 Furthermore, the reaction was highly chemoselective, reacting only with 3 2-thienyl 98 20:1 95 the aldehyde functionality. No reaction was observed with the enone 4 cyclohexyl 85 >30:1 96 functionality in the A ring (Scheme 3). 5 i-Pr 74 >30:1 97 References: (1) Review: Desimoni, G.; Faita, G.; Quadrelli, P. Chem. Rev. 2003, 103, ‑ 3119 3154. (2) Nishiyama, H.; Sakaguchi, H.; Nakamura, T.; Horihata, M.; Kondo, M.; Itoh, Table 1 K. Organometallics 1989, 8, 846‑848. (3) Nishiyama, H.; Park, S.-B.; Itoh, K. Tetrahedron: Asymmetry 1992, 3, 1029‑1034. (4) Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2002, 124, 5638‑5639. (5) Morimoto, H.; Lu, G.; Aoyama, N.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 9588‑9589. (6) Lu, J.; Hong, M.-L.; Ji, S.-J.; Loh, T.-P. Chem. ‑ O O Commun. 2005, 1010 1012. N NNIn TfO OTf OTf O OH O O N H3C H3C 20 mol% NNRh H3C H H3C H Allyltributylstannane (1.2 eq.) H Cl ClCl i-Pr i-Pr H3C TMSCl (1.2 eq.) H3C 1 mol% O OH AgBF4, Ph2SiH2 MS 4Å, CH2Cl2 O -60 °C, 30 h O R CH3 0 °C, 2-7 h R CH3 78%, >99% ee

OH OH OH Scheme 3 OH CH3 CH3 CH3

H3C CO2Et

91%, 94% ee 87%, 94% ee 93%, 92% ee 91%, 95% ee

O N O NNRh Cl ClCl O i-Pr i-Pr OH OH 1 mol% Ph Ph Ph AgBF4, Ph2SiH2 + 0 °C, 24 h 51% : 49% 99% ee 96% ee

Scheme 1

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2,6‑Bis[(4R)-(+)-isopropyl-2‑oxazolin-2‑yl]pyridine, 99% 2,6‑Bis[(4R,5R)-4‑methyl-5‑phenyl-2‑oxazolinyl]pyridine, 97% [131864‑67‑0] C17H23N3O2 O O FW 301.38 N O O N N N H3C CH3 N N CH3 H3C H3C CH3

L R: 36/37/38 S: 26-36 2,6‑Bis[(4R,5R)-4,5‑dihydro-4‑methyl-5‑phenyl-2‑oxazolyl]pyridine [312624‑05‑8] PYBOX 477494-250MG 250 mg C25H23N3O2 477494-1G 1g FW 397.47 R: 36/37/38 S: 26-36 2,6‑Bis[(4S)-(−)-isopropyl-2‑oxazolin-2‑yl]pyridine, 99% L 496081-500MG 500 mg (S,S)-2,6-Bis(4-isopropyl-2-oxazolin-2-yl) pyridine; (S,S)-2,2'-(2,6-Pyridinediyl)bis(4- O O ‑ ‑ ‑ ‑ isopropyl-2-oxazoline) N 2,6 Bis[(4S,5S)-4 methyl-5 phenyl-2 oxazolinyl]pyridine, N N [118949‑61‑4] 98% H3C CH3 C17H23N3O2 CH3 H3C FW 301.38 O O R: 36/37/38 S: 26-36 N L N N

407151-250MG 250 mg H3C CH3 407151-1G 1g 2,6‑Bis[(4S,5S)-4,5‑dihydro-4‑methyl-5‑phenyl-2‑oxazolyl]pyridine ‑ ‑ 2,6‑Bis[(4R)-4‑phenyl-2‑oxazolinyl]pyridine, 98% [185346 20 7] C25H23N3O2 (R,R)-2,6-Bis(4-phenyl-2-oxazolinyl)pyridine; (R,R)- FW 397.47 2,6-Bis(4,5-dihydro-4-phenyl-2-oxazolyl)pyridine R: 36/37/38 S: 26-36 O O L [128249‑70‑7] N N N C23H19N3O2 496103-500MG 500 mg FW 369.42 2,6‑Bis[(3aS,8aR)-3a,8a-dihydro-8H-indeno[1,2-d]oxazolin- 2‑yl]pyridine L R: 36/37/38 S: 26-36/37/39 (3aS,8aR)-in-pybox; (3aS,3′aS,8aR,8′aR)-2,2′- 496065-500MG 500 mg (2,6-Pyridinediyl)bis[3a,8a-dihydro-8H-indeno O O 496065-2G 2g [1,2-d]oxazole N N N [185346‑09‑2] 2,6‑Bis[(4S)-4‑phenyl-2‑oxazolinyl]pyridine, 98% C25H19N3O2 FW 393.44 (S,S)-2,6-Bis(4-phenyl-2-oxazolinyl)pyridine; (S,S)- 2,6-Bis(4,5-dihydro-4-phenyl-2-oxazolyl)pyridine 673978-250MG 250 mg O O [174500‑20‑0] N 673978-1G 1g N N C23H19N3O2 FW 369.42 2,6‑Bis[(3aR,8aS)-(+)-8H-indeno[1,2-d]oxazolin-2‑yl)pyridine (3aR,8aS)-in-pybox; (3aR,3′aR,8aS,8′aS)-2,2′- R: 36/37/38 S: 26-36/37/39 (2,6-Pyridinediyl)bis[3a,8a-dihydro-8H-indeno L O O [1,2-d]oxazole N 496073-500MG 500 mg N N [357209‑32‑6] 496073-2G 2g C25H19N3O2 FW 393.44

673986-250MG 250 mg 673986-1G 1g

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PHOX

Of the thousands of chiral ligands used in asymmetric synthesis a O relatively large number exhibit C2-symmetry. More recently, non-symmetrical modular P,N-ligands have been introduced Ph NP Ph PHOX independently by Pfaltz, Helmchen, and Williams and applied OTf t-Bu 1 6 mol% successfully in various metal-catalyzed reactions. These 3 mol% [Pd(dba)2] phosphinooxazolines (PHOX) are a highly versatile class of ligands.2 + O Hünig's base, benzene, 2.5 d, r.t. O PHOX ligand 43158 was successfully used in Pd-catalyzed asymmetric allylic alkylation reactions. Racemic allyl acetates were transformed into 92%, 99% ee their Pd allyl complex, which is subsequently attacked by a nucleophile to Scheme 2 give the corresponding addition adduct (Scheme 1).1 Phosphinooxazoline 688495 can induce very high enantioselectivities in the Heck reaction.3 In contrast to analogous reactions with

diphosphine-Pd catalysts, virtually no C=C double bond migration is O observed in the primary product. Hence, particularly in cases where Ph NP PF6 double bond migration leads to undesired products or mixtures of Ph Ir isomers, phosphinooxazolines are the ligands of choice (Scheme 2). R

Cationic iridium-phosphinooxazoline complexes have proved to be CH3 CH3 50 bar H2 effective catalysts for the enantioselective hydrogenation of imines and trisubstituted olefins (Scheme 3).4 In a systematic study, PHOX ligand CH2Cl2, r.t. with a bis(o-tolyl)phosphanyl moiety gave highest enantioselectivities H3CO H3CO (up to 97% ee). 75% ee (R = i-Pr) 90% ee (R = t-Bu) The cationic iridium complex with PHOX ligand 91716 is an efficient catalyst for the enantioselective intramolecular Pauson-Khand reaction.5 Scheme 3 Under optimized conditions, enantioselectivities of >90% ee were obtained with 9 mol% of catalyst (Table 1). The anion proved to be important, as it had a significant influence on the enantioselectivity

and yield. Best results obtained with relatively small, weakly O coordinating anions such as tetrafluoroborate and hexafluorophosphate, Ph NP X but also triflate. Ph Ir i-Pr Recently, Rovis et al. used PHOX ligand 688495 in a rhodium(I)-catalyzed ‑ Ph enantioselective desymmetrization reaction of meso-3,5 dimethyl Ph 9 mol% glutaric anhydride, providing rapid access to substituted syn-deoxypoly- Z R Z O 6 CO, 120 °C propionate fragments in a single transformation (Scheme 4). R

References: (1)(a) Von Matt, P.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1993, 32, 566. Entry Z R X solvent % yield %ee (b) Sprinz, J.; Helmchen, G. Tetrahedron Lett. 1993, 34, 1769. (c) Dawson, G. J.; Frost, C. 1 O H OTf DME 85 91 G.; Williams, J. M. J; Coote, S. J. Tetrahedron Lett. 1993, 34, 3149. (2) Review: Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336‑345. (3) (a) Loiseleur, O.; Meier, P.; Pfaltz, A. 2OHBFDME 89 91 Angew. Chem., Int. Ed. 1996, 35, 200. (b) Loiseleur, O.; Hayashi, M.; Schmees, N.; Pfaltz, A. 4 Synthesis 1997, 1338. (4) Lightfoot, A.; Schnider, P.; Pfaltz, A. Angew. Chem., Int. Ed. 1998, 3OHPF6 DME 93 91 37, 2897‑2899. For enantioselective reductions of imines using PHOX ligands, see: Schnider, P.; Koch, G.; Prétôt, R.; Wang, G.; Bohnen, F. M.; Krüger, C.; Pfaltz, A. Chem. — 4 NTs H OTf DME 93 81 Eur. J. 1997, 3, 887‑892. (5) Lu, Z.-L.; Neumann, E.; Pfaltz, A. Eur. J. Org. Chem. 2007, 4189‑4192. (6) Cook, M. J.; Rovis, T. J. Am. Chem. Soc. 2007, 129, 9302‑9303. 5 NTs H PF6 DME 95 77

6 C(CO2CH3)2 HBF4 THF 76 91

O 7 C(CO2CH3)2 HPF6 THF 71 91 Ph O NP O Ph 8OCH3 OTf THF 10 71 Ph Ph NP H3CO2C CO2CH3 O CH3 Pd [Pd(C3H5)]Cl (1-2 mol%) Ph 9OCHBF THF 6 64 Ph 3 4 R R H3CO2C CO2CH3 R R R R 99% ee (R = Ph) Table 1 69-79% ee (R = Alkyl) 96% ee (R = i-Pr)

Scheme 1

O Ph NP Ph t-Bu 10 mol% OOO O O 5 mol% [Rh(nbd)Cl]2

R OCH3 H3CCH3 TMSCHN2 CH CH RZnX or R2Zn (1.7 eq.) 3 3 THF, 25-50°C

F O O O O O O O O H3C OCH3 Ph AcO OCH3 OCH3 OCH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 85%, 95% ee 62%, 92% ee 78%, 91% ee 66%, 89% ee

Scheme 4

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(S)-4-tert-Butyl-2-[2-(diphenylphosphino)phenyl]-2- 8 (R)-(−)-2-[2-(Diphenylphosphino)phenyl]-4‑phenyl-2‑oxazol- oxazoline, 97% ine, ≥97.0% (31P-NMR) (4S)-tert-Butyl-2-[2-(diphenylphosphino)phenyl]-4,5- [167171‑03‑1] CH3 C27H22NOP dihydrooxazole H3C ‑ ‑ P FW 407.44 P [148461 16 9] H3C N N C H NOP 25 26 O O FW 387.45 PHOX

688495-100MG 100 mg 43158-100MG 100 mg 688495-500MG 500 mg 43158-500MG 500 mg

(R)-(+)-2-[2-(Diphenylphosphino)phenyl]-4‑isopropyl- (S)-(+)-2-[2-(Diphenylphosphino)phenyl]-4‑phenyl-2‑oxazol- 2‑oxazoline, ≥97.0% (CHN) ine, ≥97.0% (31P-NMR) (R)-(+)-2-[2-(Diphenylphosphino)phenyl]-4,5- [148461‑15‑8] dihydro-4-isopropyl-oxazole CH3 C27H22NOP ‑ ‑ P FW 407.44 P [164858 78 0] H3C N N C H NOP 24 24 O O FW 373.43

72575-100MG-F 100 mg 43160-100MG 100 mg 72575-500MG-F 500 mg 43160-500MG 500 mg

(S)-(−)-2-[2-(Diphenylphosphino)phenyl]-4‑isopropyl- 2‑oxazoline, ≥97.0% (CHN) (S)-(−)-2-[2-(Diphenylphosphino)phenyl]-4,5- dihydro-4-isopropyloxazole CH3 ‑ ‑ P [148461 14 7] H3C N C H NOP 24 24 O FW 373.43

91716-100MG-F 100 mg 91716-500MG-F 500 mg

Dynamic Kinetic Resolution Catalysts

Dynamic Kinetic Resolution (DKR) catalysis is an essential methodology for the conversion of racemic substrates into single enantiomeric products. Kim et al. reported Ph Ph the (S)-selective DKR of a variety of alcohols by utilizing the combination of substilisin NH and an aminocyclopentadienylruthenium complex. High yields and selectivities were Ph Ph Ru OC Cl obtained for a variety of secondary alcohols. CO 686190 OH O2CPr substilisin, TFEB R Ph Ph Ph Ph R Ph Ph THF Ph Ph Ph NH Ph Ph Ph H Ph Ph Ph Ph Ph Ru Ru O2CPr O2CPr O2CPr Ph Ph Ru Ru Cl OC CO OC Cl OC CO CO CO CO Shvo’s Catalyst Ph 686190 686441 668281 Cl 92%, 98% ee 92%, 99% ee 90%, 95% ee

Reference: Kim et al. J. Am. Chem. Soc. 2006, 125, 11494.

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Salen Ligands

O Salen molecules have been studied for more than six decades. However, OH O Cl O in 1990 Jacobsen and Katsuki independently published the first reports Ph Ph of salen used as ligands with manganese for asymmetric epoxidation ae Ligands Salen reactions.1 Since these first reports, the area of metal-salen catalysis has expanded greatly. A plethora of metal-salen complexes have been synthesized and used in a variety of catalyzed asymmetric 2 transformations. For example, chromium and cobalt salen complexes OO N N catalyze the epoxidation of unfunctionalized olefins with high levels of N Ph M OH OSiMe3 enantioselectivities.3 Aluminum salen complexes catalyze the conjugate H O O H CN H3C addition of azide to unsaturated imides.4 The easy synthesis and 3 3 modifications of the salen ligand framework made it the platform of choice for the discovery of new catalysts and reactions.

Examples of the versatility of the salen complexes are illustrated in OH CH3 Scheme 1. SiMe3 N3 H3C CH3 C OH References: (1)(a) Zhang, W. et al. J. Am. Chem. Soc. 1990, 112, 2801. (b) Jacobsen, E. N. 3 et al. J. Am. Chem. Soc. 1991, 113, 6703. (c) Irie, R. et al. Tetrahedron Lett. 1990, 31, 7345. (2)(a) Jacobsen, E. N. In Comprehensive Organometallic Chemistry II; Abel, E. W.; Stone, F. O OEt G. A.; Wilkinson, G., Eds.; Elsevier Science: Oxford, 1995; Vol. 12, p 1097. (b) Canali, L.; Sherrington, D. C. Chem. Soc. Rev. 1999, 28, 85. (c) McGarrigle, E. M.; Gilheany, D. G. Scheme 1 Chem. Rev. 2005, 105, 1563. (3)(a) Jacobsen, E. N. et al. J. Am. Chem. Soc. 1991, 113, 7063. (b) Jacobsen, E. N. Acc. Chem. Res. 2000, 33, 421. (4) Meyers, J.K.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 8959.

(R,R)-(−)-N,N′-Bis(3,5‑di-tert-butylsalicylidene)-1,2‑cyclo- (R,R)-N,N'-Bis(3,5‑di-tert-butylsalicylidene)-1,2‑cyclohexane- hexanediamine, 98% diaminoaluminum chloride

N N N N Al OH HO O O H3C CH3 H3C Cl CH3 H3C H3C CH3 H3C H3C CH3 H C H3C CH3 CH3 H C H3C CH3 CH3 3 CH 3 CH H3C H3C 3 H3C H3C 3

(R,R)-Jacobsen’s ligand (R,R)-N,N′-Bis(3,5‑di-tert-butylsalicylidene)-1,2‑cyclohexanediamino- [135616‑40‑9] aluminium(III) chloride C36H54N2O2 [250611‑13‑3] FW 546.83 C36H52AlClN2O2 L R: 36/37/38 S: 26 FW 607.24 R: 20/21/22 S: 26-36 404411-1G 1g L 404411-5G 5g 531960-1G 1g 531960-5G 5g (S,S)-(+)-N,N′-Bis(3,5‑di-tert-butylsalicylidene)-1,2‑cyclo- hexanediamine, 98% (S,S)-N,N'-Bis(3,5‑di-tert-butylsalicylidene)-1,2‑cyclohexane- diaminoaluminum chloride

N N N N OH HO H3C CH3 Al H3C H3C CH3 O O H3C Cl CH3 H C H3C CH3 CH3 3 CH H C H3C CH H3C H3C 3 3 3 H C H3C CH3 CH3 3 CH H3C H3C 3 (S,S)-Jacobsen’s ligand [135616‑36‑3] (S,S)-N,N′-Bis(3,5‑di-tert-butylsalicylidene)-1,2‑cyclohexanediaminoalumi- C36H54N2O2 num(III) chloride FW 546.83 [307926‑51‑8] R: 36/37/38 S: 26-36 L C36H52AlClN2O2 FW 607.24 404438-1G 1g L R: 20/21/22 S: 26-36 404438-5G 5g 531979-1G 1g

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(R,R)-N,N′-Bis(3,5‑di-tert-butylsalicylidene)-1,2‑cyclohexane- (S,S)-(+)-N,N′-Bis(3,5‑di-tert-butylsalicylidene)-1,2‑cyclo- diaminochromium(III) chloride hexanediaminocobalt(II)

N N N N Cr Co O O O O H3C Cl CH3 H3C CH3 H3C H3C CH3 H3C H3C CH3 H C H3C CH3 CH3 H C H3C CH3 CH3 3 CH 3 CH H3C H3C 3 H3C H3C 3

[164931‑83‑3] [188264‑84‑8] C36H52ClCrN2O2 C36H52CoN2O2 FW 632.26 FW 603.74 Salen Ligands L R: 20/21/22 S: 26-36 L R: 20/21/22 S: 36/37/39 531944-1G 1g 474606-1G 1g 531944-5G 5g 474606-5G 5g 474606-25G 25 g (S,S)-N,N′-Bis(3,5‑di-tert-butylsalicylidene)-1,2‑cyclohexane- diaminochromium(III) chloride (R,R)-(−)-N,N′-Bis(3,5‑di-tert-butylsalicylidene)-1,2‑cyclo- hexanediaminomanganese(III) chloride

N N

Cr N N H C O Cl O CH 3 3 Mn H C H3C 3 CH3 O O H3C Cl CH3 H C H3C CH3 CH3 3 CH H C H3C H3C 3 H3C 3 CH3 H C H3C CH3 CH3 3 CH H3C H3C 3 [219143‑92‑7] C36H52ClCrN2O2 Jacobsen’s catalyst; (R,R)-Jacobsen’s catalyst FW 632.26 [138124‑32‑0] R: 20/21/22 S: 26-36 L C36H52ClMnN2O2 FW 635.20 531952-1G 1g R: 36/37/38 S: 26-36 531952-5G 5g L 404446-1G 1g (R,R)-(−)-N,N′-Bis(3,5‑di-tert-butylsalicylidene)-1,2‑cyclo- 404446-5G 5g hexanediaminocobalt(II) 404446-25G 25 g

(S,S)-(+)-N,N′-Bis(3,5‑di-tert-butylsalicylidene)-1,2‑cyclo- hexanediaminomanganese(III) chloride N N Co O O H3C CH3 H3C H3C CH3 H C H3C CH3 CH3 N N 3 CH H3C H3C 3 Mn H C O O ‑ ‑ 3 Cl CH3 [176763 62 5] H3C H3C CH3 H C CH3 CH3 C36H52CoN2O2 H3C 3 H C H3C CH3 FW 603.74 3 R: 20/21/22 S: 36/37/39 L (S,S)-Jacobsen’s catalyst ‑ ‑ 474592-1G 1g [135620 04 1] C36H52ClMnN2O2 474592-5G 5g FW 635.20 474592-25G 25 g L R: 36/37/38 S: 26-36 404454-1G 1g 404454-5G 5g 404454-25G 25 g

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2,2′-[(1S,2S)-(+)-1,2‑Cyclohexanediylbis[(E)(nitrilomethyl- 2,2′-[(1S,2S)-1,2‑Cyclohexanediylbis[(E)-(nitrilomethylidyne)]]bis[4-(tert-butyl)-6-(4‑morpholinylmethyl)morpho- idyne)]]bis[4-(tert-butyl)-6-(4‑piperidinylmethyl)phenol], linylmethyl)phenol], 97% 97% N,N′-Bis[(E)-5-(tert-butyl)-2-hydroxy-3,4-morpho- N,N′-Bis[(E)-5-(tert-butyl)-2-hydroxy-3-4- CH3 CH3 H C H3C linylmethyl)benzylidene]-[(1S,2S)-1,2-cyclohexane- 3 CH3 piperidinylmethyl)benzylidene]-[(1S,2S)-1,2-cyclo- CH3 ae Ligands Salen diamine] hexanediamine] ‑ ‑ O ‑ ‑ [252735 72 1] N [478282 27 8] N C38H56N4O4 C40H60N4O2 N OH FW 632.88 N OH FW 628.93

N OH N OH

N N O

CH3 H C CH3 H3C 3 CH3 CH3 L R: 36/37/38 S: 26 L R: 36/37/38 S: 26 673366-250MG 250 mg 673358-250MG 250 mg ′ ‑ 2,2′-[(1R,2R)-(–)-1,2‑Cyclohexanediylbis((E)-(nitrilomethyl- 2,2 -[(1R,2R)-1,2 Cyclohexanediylbis[(E)(nitrilomethylidyne)] ‑ idyne))]bis[4-(tert-butyl)-6-(4‑morpholinylmethyl)phenol], bis[4-(tert-butyl)-6-(4 piperidinylmethyl)phenol], 97% 97% N,N′-Bis[(E)-5-(tert-butyl)-2-hydroxy-3-4- CH3 H3C N,N′-Bis[(E)-5-(tert-butyl)-2-hydroxy-3-(4-morpho- piperidinylmethyl)benzylidene]-[(1R,2R)-1,2-cyclo- CH3 CH3 H3C hexanediamine] linylmethyl)benzylidene]-[(1R,2R)-1,2-cyclohexane- CH3 ‑ ‑ diamine] O [478282 28 9] N N C H N O [323193‑85‑7] 40 60 4 2 N OH N OH FW 628.93 C38H56N4O4 FW 632.88 N OH N OH N N O CH CH H3C 3 H3C 3 CH CH3 3 L R: 36/37/38 S: 26 L R: 36/37/38 S: 26 673331-250MG 250 mg 673374-250MG 250 mg

Chiral Diene Ligands

The use of chiral diene as ligands for asymmetric synthesis has been growing for the past 5 years. Paquin et al. reported the asymmetric synthesis of 3,3-diarylpropanals using a H3C OCH3 chiral bicyclo[2.2.2]octadiene as a ligand with a rhodium complex. This new synthesis H Ph provides access to building blocks that are otherwise not readily available. Good yields and CH3 selectivity were reported with a variety of boronic acids and cinnamaldehydes. H3C CH3 Reference: Carreira, E. M. et al J. Am. Chem. Soc. 2005, 127, 10850. 672254

(3.3 mol%) H C OCH H C OCH [(Rh(C2H4)Cl]2 (3 mol%) Ar' 3 3 3 3 KOH H CHO Ar' B(OH) CHO H Ar + 2 Ar Ph CH3 Ph CH 3 MeOH/H2O H3C CH3 CH3 50 °C CH3

672254 669490 H3C O OCH3 CF3

Ph H Ph H

CHO CHO CHO

H Ph H Ph H3CO 698725 698733 80%, 92% ee 78%, 93% ee 85%, 90% ee

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Cinchona Alkaloids

Cinchona alkaloids and their derivatives have proven to catalyze an The metal-free, allylic amination reaction provides a useful extension to astonishing array of enantioselective transformations, providing access to the conventional palladium catalyzed π-allylic methodology. Amination chiral products of high enantiopurity.1 The presence of the tertiary with diimides at the remote γ-position can be carried out using quinuclidine nitrogen renders them effective ligands for a variety of (DHQ)2PYR (418978) to form a diverse range of highly functionalized metal-catalyzed processes. Of these reactions, the osmium-catalyzed amine compounds (Scheme 5).7 asymmetric dihydroxylation of olefins (Scheme 1), developed by 2 Jørgensen et al. have developed the first catalytic enantioselective Sharpless in 1988, has had the greatest impact in synthetic chemistry. 8 conjugate addition to alkynones using (DHQ)2PHAL (392723). For both Bis-(cinchona alkaloid) ligands (which are generally the better catalysts) aromatic and aliphatic alkynones the addition of β-diketones proceeds in catalyze the formation of diols of high enantiopurity from a very broad high yields and enantioselectivity giving a mixture of (E)- and (Z)-enones range of olefins. A recent example stems from O'Doherty et al. where (Scheme 6). (E,E)- and (E,Z)-1,3‑dienoates were dihydroxylated regioselectively in Dimeric (DHAD) AQN catalyzes the enantioselective desymmetrization of good yields and excellent enantioselectivities using (DHQD) PHAL 2 2 meso anhydrides with methanol by a nucleophilic mechanism 392731 (Scheme 2).3 (Scheme 7). The scope of the reaction was found to be very general, Subsequently, these cinchona alkaloids were used for the with excellent enantioselectivity obtained in the desymmetrization of Cinchona Alkaloids osmium-catalyzed asymmetric aminohydroxylation of olefins.4 The monocyclic, bicyclic, and tricyclic prochiral and meso anhydrides.9 significance of this reaction is immediately apparent as the asymmetric aminohydroxylation provides straightforward access to the References: (1) Kacprzak, K.; Gawronski, J. Synthesis 2001, 961‑998. (2) Kolb, H. C.; aminoalcohols present in a wide variety of biologically active agents VanNieuwenhze, M. S.; Sharpless, K. B. Chem.Rev. 1994, 94, 2483. (3) Ahmed, Md. M.; ‑ and natural products. Mortensen, M. S.; O'Doherty, G. A. J. Org. Chem. 2006, 71, 7741 7746. (4) Bodkin, J. A.; McLeod, M. D. J. Chem. Soc., Perkin Trans. 1, 2002, 2733‑2746. (5) Kim, G.; Kim, N. Kim et al. have published recently a practical new synthetic route to Tetrahedron Lett. 2007, 48, 4481‑4483. (6) Tian, S.-K.; Hong, R.; Deng, L. J. Am. Chem. (–)-cassine, which shows antimicrobial activity against Staphylococcus Soc. 2003, 125, 9900‑9901. (7) Poulsen, T.B.; Alemparte, C.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 11614‑11615. (8)(a) Bella, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, aureus, via asymmetric aminohydroxylation followed by reductive ‑ 5 126, 5672 5673. (b) Chen, Y.; Tian, S.-K.; Deng, L. J. Am. Chem. Soc. 2000, 122, amination (Scheme 3). 9542‑9543. The nucleophilic quinuclidine nitrogen can also be used directly as a reactive center for enantioselective catalysis. Cinchona alkaloids HO OH therefore can be used as bases to deprotonate substrates with relatively RS RM acidic protons forming a contact ion pair between the resulting anion AD-mix α R R RL H and protonated amine. This interaction leads to a chiral environment S M around the anion and permits enantioselective reactions with RL H AD-mix β electrophiles. RL H RS RM Important in many of these processes is the ability to control the HO OH formation of quaternary asymmetric centers with high enantiomeric Scheme 1 excesses. Using the (DHQD)2AQN (456713) catalyst it is possible to affect the α-functionalization of ketones by the addition of TMSCN to the corresponding cyanohydrin in excellent yield and enantiomeric excess (Scheme 4).6

1% OsO , 5% (DHQD) PHAL O 4 2 OH O 3 eq. K3Fe(CN)6, 3 eq. K2CO3, 3 eq. MeSO2NH2 R OEt R OEt 0.2 M t-BuOH/H2O (1:1), 0° to r.t. CH3 HO CH3 68%, 99% ee (R = CH3) 70%, 98% ee (R = (CH2)2OTBS) 73%, 99% ee (R = (CH2)2OBn)

1% OsO4, 5% ligand CH3 O OH O 3 eq. K3Fe(CN)6, 3 eq. K2CO3, 3 eq. MeSO2NH2

OEt H3C OEt 0.2 M t-BuOH/H2O (1:1), 0° to r.t. CH3 HO CH3

35%, 70% ee (ligand (DHQD)2PHAL) 64%, 73% ee (ligand (DHQD)2PYR)

Scheme 2

OO Z-NH2, NaOH, t-BuOCl NHZ O O K2OsO4•2H2O/(DHQD)2PHAL (cat.) H3C CH3 H3C 10 CH3 10 BuOH/H2O, r.t. OH

43%, 86% ee

H2, Pd/C (cat.) MeOH, r.t.

HO O

H3C N 10 CH3 H (−)-cassine, 85%

Scheme 3

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H H CH3H3C O 2-20 mol% cat. NC OTMS N N OEt OEt O O Ph Ph H H TMSCN, CHCl3, -50° H CO OEt OEt 3 OO OCH3

>80% N N Alkaloids Cinchona 90-98% ee

(DHQD)2AQN

Scheme 4

CH3 H3C 1 R1 N R Boc N 2 10 mol% RO C R2 O O RO2C R + NN 2 H H H CO NN OCH Boc CH2Cl2, -24° CN N 3 3 CN NHBoc Boc N 65-80% 86-99% ee (DHQ)2PYR

Scheme 5

H H H C 3 CH3 O O N O O N O OONN 5 mol% R1 H H R1 + R2 H3CO OCH3 toluene, r.t. O NN R2 >95% (DHQ)2PHAL 77-95% ee

Scheme 6

O (+)-Cinchonine, 85% H3C H3CCO2H (DHQD)2AQN (5-30 mol%) O Cinchonine monohydrochloride dihydrate H C MeOH, toluene, -40 to -20°C H C CO CH 2 H3C 3 2 3 [118‑10‑5] O C19H22N2O N

H H FW 294.39 OH CO2H CO2H H3CCO2H O H3C CO2H CO2H N CO CH CO CH H3C CO2CH3 CO2CH3 H3C CO2CH3 H 2 3 H 2 3 99%, 95% ee 97%, 97% ee 93%, 98% ee 88%, 96% ee 72%, 90% ee L R: 20/22 S: 26-36 EC No. 204-234-6 RTECS # GD3500000 Scheme 7 857270-25G 25 g 857270-100G 100 g 857270-250G 250 g Cinchonidine, 96% (−)-Cinchonidine Cinchonine monohydrochloride hydrate, 99% ‑ ‑ H2C [485 71 2] Cinchonan-9(S)-ol monohydrochloride H C C19H22N2O N [312695‑48‑0] 2 FW 294.39 N • HCl OH C19H22N2O · HCl · xH2O FW 330.85 (Anh) OH • xH2O N N S: 22-24/25 EC No. 207-622-3 RTECS # GD2975000 R: 20/21/22 S: 36 C80407-10G 10 g L C80407-100G 100 g 420328-50MG 50 mg 420328-250MG 250 mg

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Quinidine, ≥98.0% (NT, dried material) Hydroquinidine, 95% [56‑54‑2] Dihydroquinidine H2C H3C C20H24N2O2 [1435‑55‑8] FW 324.42 N C20H26N2O2 N FW 326.43 H3CO OH H3CO OH

N N L R: 22 S: 36 EC No. 200-279-0 RTECS # VA4725000 L R: 20/21/22 S: 36/37 EC No. 215-862-5 RTECS # MX3016000 22600-10G-F 10 g 359343-1G 1g 22600-50G-F 50 g 359343-5G 5g

Quinine, 90% Hydroquinine, 98% [130‑95‑0] Dihydroquinine H2C H3C C20H24N2O2 [522‑66‑7] FW 324.42 N Cinchona Alkaloids C20H26N2O2 N H3CO OH FW 326.43 H3CO OH N N L R: 36/37/38-42/43 S: 22-26-36/37-45 EC No. 205-003-2 RTECS # VA6020000 L R: 36/37/38 S: 26-36 EC No. 208-334-0 145904-10G 10 g 337714-1G 1g 145904-50G 50 g 337714-5G 5g

Quinine hemisulfate salt monohydrate, 90% Hydroquinidine hydrochloride, 98%

H2C Dihydroquinidine hydrochloride H3C • 1/2 H2SO4 [1476‑98‑8] N • H O C20H26N2O2 · HCl N 2 • HCl H3CO OH FW 362.89 H3CO OH N N ‑ ‑ [6119 70 6] R: 22 EC No. 216-024-1 RTECS # MX3018000 C20H24N2O2 · 0.5H2O4S·H2O L FW 391.47 254819-5G 5g R: 36/37/38 S: 26 L 254819-25G 25 g 145912-5G 5g 145912-10G 10 g Hydroquinine hydrobromide hydrate, 98% 145912-50G 50 g ‑ ‑ [207386 86 5] H C C H N O · HBr · xH O 3 20 26 2 2 2 • HBr ≥ FW 407.34 (Anh) N Hydrocinchonine, 97.0% (GC, sum of enantiomers) • xH O H3CO OH 2 Dihydrocinchonine H3C N [485‑65‑4] C19H24N2O N L R: 36/37/38 S: 26-37/39 FW 296.41 OH 341320-1G 1g N ‑ ≥99.0% (NT) O-(4 Chlorobenzoyl)hydroquinine, 98% R: 20/21/22 S: 36/37 EC No. 207-621-8 Dihydroquinine 4-chlorobenzoate; Hydroquin- L H3C ine 4-chlorobenzoate 54060-500MG 500 mg [113216‑88‑9] N Cl C H ClN O 27 29 2 3 H CO O FW 464.98 3 O N

S: 22-24/25 336491-1G 1g

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Hydroquinidine 4‑chlorobenzoate, 98% (2R,4S,5R)-2‑Aminomethyl-5‑ethylquinuclidine, ≥95.0% (GC) Dihydroquinidine 4-chlorobenzoate; O-(4- (2R,4S,5R)-5-Ethyl-2-quinuclidinylmethylamine H C H C Chlorobenzoyl)hydroquinidine 3 [475160‑61‑3] 3 ‑ ‑ N [113162 02 0] N Cl C10H20N2 H2N FW 168.28 C27H29ClN2O3 O H CO Alkaloids Cinchona FW 464.98 3 R: 22-37/38-41 S: 26-39 O L N 39867-100MG-F 100 mg L R: 36/37/38 S: 26-36 39867-500MG-F 500 mg 336483-1G 1g (2S,4S,5R)-2‑Aminomethyl-5‑ethylquinuclidine, ≥95.0% (GC) 336483-5G 5g (2S,4S,5R)-5-Ethyl-2-quinuclidinyl-methylamine ‑ ‑ H3C Hydroquinine 4‑methyl-2‑quinolyl ether, 98% [475160 59 9] C10H20N2 N [135096‑79‑6] FW 168.28 H C 3 H2N C30H33N3O2 FW 467.60 N L R: 22-38-41 S: 26-39 H3CO O N 07317-100MG-F 100 mg N CH3 07317-500MG-F 500 mg

R: 36/37/38 S: 26-36 L (2R,4S,5R)-2‑Hydroxymethyl-5‑ethylquinuclidine, ≥99.0% 381969-1G 1g (GC) (2R,4S,5R)-5-Ethyl-2-quinuclidinylmethanol H C Hydroquinidine 4‑methyl-2‑quinolyl ether, 97% [219794‑81‑7] 3 C H NO N [135042‑89‑6] 10 19 HO H C FW 169.26 C H N O 3 30 33 3 2 R: 37/38-41 S: 26-39 FW 467.60 N L

H3CO O N 49463-100MG-F 100 mg 49463-500MG-F 500 mg N CH3 ‑ ‑ ≥ R: 36/37/38 S: 26-36 (2S,4S,5R)-2 Hydroxymethyl-5 ethylquinuclidine, 99.0% L (GC) 381942-1G 1g (2S,4S,5R)-5-Ethyl-2-quinuclidinylmethanol H C [219794‑79‑3] 3 Hydroquinidine 9‑phenanthryl ether, 96% C10H19NO N FW 169.26 O-(9-Phenanthryl)hydroquinidine HO H C [135042‑88‑5] 3 R: 37/38-41 S: 26-39 C34H34N2O2 N L FW 502.65 H3CO O 51957-100MG-F 100 mg

N 51957-500MG-F 500 mg

S: 22-24/25 (2R,5R)-(+)-5‑Vinyl-2‑quinuclidinemethanol, 96%

381950-250MG 250 mg C10H17NO H2C 381950-1G 1g FW 167.25 N

Hydroquinine-9‑phenanthryl ether, 97% OH O-(9-Phenanthryl)hydroquinine H C Fp: 113 °C (235 °F) [135096‑78‑5] 3 472549-250MG 250 mg C34H34N2O2 N FW 502.65 H3CO O

L R: 36/37/38 S: 26-36 381977-100MG 100 mg 381977-500MG 500 mg

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(DHQ)2AQN, 95% (DHQ)2PHAL, ≥95%

H3C CH3 H3C CH3 N N N N O O NN O O H3CO O O OCH3 H3CO OCH3

N N N N

Hydroquinine anthraquinone-1,4‑diyl diether Hydroquinine 1,4‑phthalazinediyl diether [176097‑24‑8] [140924‑50‑1] C54H56N4O6 C48H54N6O4 FW 857.05 FW 778.98 L R: 36/37/38 S: 26-36/37 S: 22-24/25 392723-500MG 500 mg 456705-500MG 500 mg

(DHQ)2Pyr, 97%

Cinchona Alkaloids (DHQD)2AQN, 95%

H3C CH3 CH H C N 3 3 N N N O O O O H CO NN OCH H3CO O O OCH3 3 3

N N N N

‑ Hydroquinidine (anthraquinone-1,4 diyl) diether Hydroquinine 2,5‑diphenyl-4,6‑pyrimidinediyl diether ‑ ‑ [176298 44 5] [149820‑65‑5] C54H56N4O6 C56H60N6O4 FW 857.05 FW 881.11 R: 36/37/38 S: 26-36 L L R: 36/37/38 S: 26-36 456713-500MG 500 mg 418978-250MG 250 mg 418978-1G 1g (DHQD)2PHAL, ≥95% AD-mix-α H3C N CH3 N

NN H3C O O CH3

H3CO OCH3 N NN N N N H H H3CO OCH3 Hydroquinidine 1,4‑phthalazinediyl diether [140853‑10‑7] N N C48H54N6O4 FW 778.98 392758-10G 10 g S: 22-24/25 392758-50G 50 g 392731-1G 1g AD-mix-β (DHQD)2Pyr, 97% H3C CH3

N N CH N NN N 3 H3C O O H H H3CO OCH3 H3CO NN OCH3 N N N N

392766-10G 10 g Hydroquinidine-2,5‑diphenyl-4,6‑pyrimidinediyl diether 392766-50G 50 g [149725‑81‑5] C56H60N6O4 FW 881.11 L R: 36/37/38 S: 26-36 418951-1G 1g

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QuinoxP* Ligands

Various optically active phosphine ligands incorporating a chiral center at t-Bu CH3 N P the phosphorus display exceptional enantiosectivities in metal-catalyzed 1 asymmetric synthesis. For instance, known classes of P-chiral phosphine N P NHAc NHAc Ligands QuinoxP* ligands offer good to excellent enantiocontrol in Ru- and Rh-catalyzed H3C t-Bu R2 * R2 hydrogenation reactions.2 The one limitation associated with these R1 R1 1 mol% [Rh(nbd) ]BF ligands is their sensitivity to air, which has impeded widespread R3 2 4 R3 H2, MeOH, 6 h applicability in bench-top chemistry. Imamoto and co-workers have 96 - 99% ee addressed this deficiency through the invention of QuinoxP*, which Scheme 1 contains an electron-withdrawing quinoxaline architecture.3 The reactivity profile of these innovative, chiral ligands is presented and highlights the impressive breadth of valuable transformations mediated by QuinoxP*. These powerful efficient ligands exhibit high levels of Entry R1 R2 R3 ee (%) (conﬁ g) enantiocontrol in synthetic transformations ranging from metal-catalyzed 1COCH Ph H 99.9 (R) asymmetric 1,4‑additions of arylboronic acids, to enantioselective 2 3 3 alkylative ring opening, to asymmetric hydrogenations. It is worth 2CO2CH3 4-AcO-3-MeOC6H3 H 99.6 (R) noting that QuinoxP* is not oxidized at the stereogenic phosphorus 3CH HCOCH 99.7 (R) center on standing at ambient temperature in air for more than 3 2 3

9 months. 4CH3 CO2CH3 H 99.2 (R) 5 Ph H H 99.9 (R) Highly Asymmetric 6 1-adamantyl H H 99.3 (S) Rhodium-Catalyzed Hydrogenation Imamoto has gone to great lengths to develop enantiomerically pure Table 1 P-chiral ligands for industrially useful transformations such as asymmetric hydrogenation. Impressively, a diverse array of prochiral amino acid and amine substrates were hydrogenated with great efficiency to yield highly t-Bu CH3 enantiopure amine derivatives (Scheme 1). The authors carried out these N P experiments at room temperature in methanol under low hydrogen pressures (3 atm). Note that all hydrogenation reactions were complete N P in 6 hours and with enantiomeric excesses ranging from 96 to 99.9%. H3C t-Bu Dramatic stereochemical reversal, consistent with the results observed (3 mol%) with the related (S,S)-tert-Bu-BisP* ligands,4,5 was obtained when ‑ ‑ OO[RhCl(C2H4)2]2 (3 mol%) Ph 1 acetylamino-1 adamantylethene was hydrogenated to afford the PhB(OH)2, KOH , dioxane/H2O, 1 h S configuration amine with >96% enantioselectivity (Table 1). 97%, 99% ee Scheme 2 Asymmetric 1,4‑additions of Arylboronic Acids Imamoto and co-workers exploited the high activity of the QuinoxP* ligand in rhodium-catalyzed enantioselective 1,4‑additions of arylboronic t-Bu CH3 acids to α,β-unsaturated carbonyl substrates.3 High yields of the addition N P products were obtained via running the reactions between 40 and N P 50 ºC (Scheme 2). The exceptional enantiocontrol exerted by this H3C t-Bu Rh(I)-catalyzed system is evident when compared to the use of BINAP as OH 1 2 the chiral ligand.6 R (5 mol%) R O 1 R PdCl2(cod) (5 mol%) 2 Asymmetric Pd-catalyzed Ring Opening R 2Zn, Ch2Cl2, rt Imamoto and co-workers have also succeeded in developing a Scheme 3 Pd-catalyzed C–C bond-forming reaction, which displays high enantioselectivities with both dimethyl- and diethylzinc (Scheme 3, Table 2). This alkylative ring-opening methodology entails simply 1 2 premixing PdCl2(cod) and QuinoxP* for 2 hours at room temperature— Entry R R Time (h) Yield (%) ee (%) (conﬁ g) leading to a highly active catalyst. This catalyst system affords excellent 1H CH 2 90 95.6 yields of the ring-opened products and selectivities that rival the highest 3

reported for this transformation. These results, when combined with the 2HCH2CH3 15 88 97.6 outstanding methodologies presented, indicate that QuinoxP* is useful for a broad variety of asymmetric metal-catalyzed transformations. 3F CH3 2 90 93.8

References: (1)(a) Weinkauff, D. J. et al. J. Am. Chem. Soc. 1977, 99, 5946. (b) Spagnol, Table 2 M. et al. Chem. -Eur. J. 1997, 3, 1365; (c) Hamada, Y. et al. Tetrahedron Lett. 1997, 38, 8961; (d) Kurth, V. et al. Eur. J. Inorg. Chem. 1998, 597. (e) Mezzetti, A. et al. Organometallics 1998, 17, 668. (f) Imamoto, T. et al. J. Am. Chem. Soc. 1998, 120, 1635. (g) Mezzetti, A. et al. Organometallics 1999, 18, 1041. (h) Imamoto, T. J. Org. Chem. 1999, 64, 2988. (i) Imamoto, T. et al. Tetrahedron: Asymmetry 1999, 10, 877. (j) van Leeuwen, P. W. N. M. et al. J. Org. Chem. 1999, 64, 3996. (2) (a) Zhang, Z. et al. J. Org. Chem. 2000, 65, 6223. (b) Tang, W. et al. J. Am. Chem. Soc. 2003, 125, 9570. (c) Lei, A. et al. J. Am. Chem. Soc. 2004, 126, 1626. (d) Tang, W.; Zhang, X. Angew. Chem., Int. Ed. Engl. 2002, 41, 1612. (e) Tang, W.; Zhang, X. Org. Lett. 2002, 4, 4159. (f) Tang, W. et al. Org. Lett. 2003, 5, 205. (g) Tang, W. et al. Angew. Chem., Int. Ed. 2003, 42, 3509 (h) Xiao, D. et al. Org. Lett. 1999, 1, 1679. (i) Liu, D.; Zhang, X. Eur. J. Org. Chem. 2005, 646. (3) Imamoto, T.; Sugita, K.; Yoshida, K. J. Am. Chem. Soc. 2005,127, 11934. (4) Imamoto, T. et al. J. Am. Chem. Soc. 2000, 122, 10486. (5) Imamoto, T. et al. J. Am. Chem. Soc. 2001, 123, 5268. (6)(a) Miyaura, N. et al. J. Am. Chem. Soc. 1998, 120, 5579. (b) Hayashi, T. et al. Tetrahedron Lett. 1999, 40, 6957.

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(S,S)-2,3-Bis(tert-butylmethylphosphino) quinoxaline 8 (R,R)-(–)-2,3‑Bis(tert-butylmethylphosphino)quinoxaline, 97% (S) QuinoxP® H3C CH3 ® C18H28N2P2 H3C (R) QuinoxP H3C FW 334.38 CH3 N P CH3 C18H28N2P2 H3C FW 334.38 N P CH3 N P CH3

H3C N P CH3 CH3 H3C H3C CH3 H3C L R: 22-36/37/38 S: 26 R: 22-36/37/38 694215-100MG 100 mg L 676403-100MG 100 mg 676403-500MG 500 mg QuinoxP* Ligands

Explore Organocatalysis

Vol. 7, No. 9

Organocatalysis Organocatalysis provides convenient new methods to construct complex chiral compounds with operational simplicity and without the need for metals. Excellent selectivities are observed in various asymmetric organocatalyzed transformations.

Features include: • Proline Analogs • MacMillan Imidazolidinone ™ OrganoCatalysts ® • Chiral Phosphoric Acids • Jacobsen Thioureas Sigma-Aldrich is pleased to offer an expanding portfolio of innovative

L-Proline, the archetype of modern asymmetric • Cinchona Alkaloids organocatalysts organocatalysts to accelerate your research success.

CF3

CF3 O O P O OH

CF3 O N N N N H OH H HN N CF3 P0380 684341 681520

CH3 CF3

• HCl N CH3 N CF3 N O O O CH3 H Si CH3 H Si CH3 H Si CH CH CH3 3 3 CH3 CH3 CH3 H3C CH3 F3C CF3 677183 671428 677019

To see a comprehensive listing of organocatalysts, please visit sigma-aldrich.com/organocat

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DIPAMP

Rewarded by a Nobel Prize in 2001 for his pioneering work in asymmetric (R,R)-DIPAMP, ≥95% synthesis, Knowles was the first to develop a transition-metal chiral − catalyst based on a chiral diphosphine ligand, DIPAMP, that could transfer [(1R,2R)-( )-Bis[(2-methoxyphenyl)phenylphos- DIPAMP/DIOP chirality to a prochiral substrate with high enantiomeric excesses. He phino]ethane]; (R,R)-Ethylenebis[(2-methoxyphenyl)phenylphosphine] H3CO demonstrated that a chiral diphosphine chelated to rhodium could give P access to catalysis mimicking enzyme selectivity. To demonstrate the [55739‑58‑7] P OCH3 activity and selectivity of this new ligand, Knowles synthesized L-DOPA, a C28H28O2P2 treatment for Parkinson's disease, requiring the selective hydrogenation FW 458.47 of an alkene. The synthesis of L-DOPA starts with the asymmetric hydrogenation of (Z)-2‑acetamido-3-(3,4‑dihydroxyphenyl)acrylic acid L R: 36/37/38 S: 26-36/37 using the Rh-DIPAMP complex followed by deprotection of the amine. This process has been scaled up at Monsanto (Scheme 1).1 461865-500MG 500 mg 461865-1G 1g Reference: (1) Knowles, W. S. Acc. Chem. Res. 1983, 16, 106. (S,S)-DIPAMP (1S,2S)-(+)-Bis[(2-methoxyphenyl)phenylphos- P phino]ethane H CO 3 Rh [97858‑62‑3] H3CO P P C28H28O2P2 P OCH O O FW 458.47 3 HO H3CO HO OH OH HN O HN O H HO HO 2 ≥ 95% ee 95% 461873-250MG 250 mg 461873-1G 1g

O HO OH NH HO 2 L-DOPA

Scheme 1

DIOP

DIOP is one of the first chiral ligands used for asymmetric hydrogenation (+)-2,3-O-Isopropylidene-2,3‑dihydroxy-1,4‑bis(diphenyl- catalysis. DIOP can be synthesized in four simple steps from tartaric acid. phosphino)butane, 98% Chelation with a rhodium complex generates an optically active catalyst active in hydrogenation. To demonstrate the activity of DIOP, Kagan and (+)-1,4-Bis(diphenylphosphino)-1,4-dideoxy-2,3-O- Dang conducted the asymmetric hydrogenation of a variety of alkenes.1 isopropylidene-D-threitol; (4S,5S)-4,5-Bis(diphenyl- Optical yields of up to 72% were obtained with substrate to catalyst ratio phosphinomethyl)-2,2-dimethyl-1,3-dioxolane; (S,S)- P P of up to 200:1 (Scheme 1). DIOP; (4S-trans)-[(2,2-Dimethyl-1,3-dioxolane-4,5- diyl)bis(methylene)]bis(diphenylphosphine); (+)-DIOP O O H C CH References: (1)(a) Dang, T. P.; Kagan, H. B. Chem. Commun. 1971, 481. (b) Kagan, H. B.; [37002‑48‑5] 3 3 Dang, T. P. J. Am. Chem. Soc. 1972, 94, 6429. C31H32O2P2 FW 498.53 R: 36/37/38 S: 26 EC No. 253-307-9 O L HN 237663-50MG 50 mg CH3 H CONH2 237663-1G 1g 72%, 71% ee (−)-2,3-O-Isopropylidene-2,3‑dihydroxy-1,4‑bis(diphenylphosphino)butane, 98%

O Ph2P PPh2 O (4R,5R)-4,5-Bis(diphenylphosphino-methyl)-2,2- HN HN dimethyl-1,3-dioxolane; (4R-trans)-[(2,2-Dimethyl- ∗ Ph OO ∗ CH3 H COOH H COOH 1,3-dioxolane-4,5-diyl)bis(methylene)]bis(diphenyl- H3C CH3 P P 96%, 64% ee 95%, 72% ee phosphine); (R,R)-DIOP; (−)-1,4-Bis(diphenylphosphino)-1,4-dideoxy-2,3-O-isopropylidene-L-threitol OO [32305‑98‑9] H3C CH3 O C31H32O2P2 HN FW 498.53 ∗ CH3 R: 36/37/38 S: 26-36/37 EC No. 250-984-2 H COOCH3 L 90%, 55% ee 237655-250MG 250 mg Scheme 1 237655-1G 1g

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Trost Ligands

Palladium-catalyzed asymmetric allylic alkylation (AAA) has proven to be Oxygen Nucleophiles an exceptionally powerful method for the efficient construction of stereogenic centers. In sharp contrast to many other catalytic methods, Carbon-oxygen bond-forming reactions using palladium-catalyzed AAA has the ability to form multiple types of bonds (C–C, C–O, C–S, asymmetric allylic alkylation have been well-demonstrated in C–N) with a single catalyst system. numerous natural product syntheses. Alcohols, carboxylates, and hydrogencarbonates have all been employed as O-nucleophiles.

R R' * ArOH Nu or O ArO O high yields and * RX O Pd2(dba)3•CHCl3 O enantioselectivities RR'* PdLn BocO (R,R)-DACH-ligand H R' TBAC, CH Cl Nu 2 2 intermediates to brefeldin A complexation and aflatoxin B1 Trost Ligands * * * 4 LnPd PdLn LnPd Alcohol Nucleophiles RR'* R * R' RX or Nu Nu R'

CO2CH3 CO2CH3 PdL* –X n t-BuCO2Na O RR' ionization Pd (dba) •CHCl (2.5 mol %) Nu OCO2CH3 2 3 3 O t-Bu (R,R)-DACH-phenyl (7.5 mol %) racemic THAB, CH2Cl2 98%, 93% ee nucleophilic addition * PdLn (+)-phyllanthocin R intermediate R' Carboxylate Nucleophiles5

The Trost group at Stanford University has pioneered the use of C-2 symmetric diaminocyclohexyl (DACH) ligands in AAA, allowing for the rapid synthesis of a diverse range of chiral products with a limited Nitrogen Nucleophiles number of chemical transformations. Reactions are typically 1 A formidable challenge in asymmetric synthesis is the stereocontrolled high-yielding, and excellent levels of enantioselectivity are observed. construction of carbon-nitrogen bonds. Nitrogen nucleophiles such as

DACH-Phenyl DACH-Naphthyl DACH-Pyridyl alkylamines, azides, amides, imides, and N-heterocycles have all been employed in asymmetric allylic alkylation reactions.

O O O O O O APC H NH HN NH HN NH HN S,S NH (S,S)-DACH-phenyl N PPh2 Ph2P PPh2 Ph2P N N PMB OAc THF, NEt3 PMB 97%, 91% ee

Alkylamines Nucleophiles6 O O O O O O NH HN NH HN NH HN

R,R PPh2 Ph2P PPh2 Ph2P N N

OCO2CH3 OCO2CH3 O O TMSN3 O APC (0.25 mol%) O (R,R)-DACH-phenyl (0.75 mol %) OCO2CH3 N3 Carbon Nucleophiles CH2Cl2, rt 82%, 95% ee In early examples of this methodology, Trost and co-workers demonstrated diesters are competent nucleophiles for the deracemization of (+)-pancratistatin intermediate cyclic allylic acetates, to afford chiral malonate derivatives. Since that Azide Nucleophiles7 time, soft carbon nucleophiles such as barbituric acid derivatives, β-keto esters, nitro compounds, and many others have been employed in AAA for assembly of tertiary and quaternary asymmetric centers. TsHN(O)CO Pd2(dba)3•CHCl3 (2.5 mol%) O O Na O or O E DACH-phenyl ligand N N EE Ts OAc * for n = 1, intermediate to (7.5 mol %) Ts α TsHN(O)CO E isoiridomyrmecin, - Et3N, CH2Cl2 95%, 97% ee ( )n APC ( ) n skyanthine, and 12- DACH-phenyl ligand intermediates to mannostatin A n = 1, 2, 3 oxophytodienoic acid THAB, CH2Cl2 81–86%, 93–98% ee and (–)-swainsonine

E = CO2CH3 Imide Nucleophiles8 Malonate Nucleophiles2

CO2Et H O N CO2Et steps OAc APC (0.5 mol %) OH (S,S)-DACH-phenyl (1.5 H 81%, 86% ee mol %) (–)-nitramine TMG, toluene, 0 ºC

β-Keto Ester Nucleophiles3

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Molybdenum-Catalyzed Reactions References: (1)(a) Trost, B. M.; Fandrick, D. R. Aldrichimica Acta 2007, 40, 59. (b) Trost, B. The mechanism of the molybdenum-catalyzed AAA reaction is presumed M. et al. Acc. Chem. Res. 2006, 39, 747. (c) Trost, B. M. J. Org. Chem. 2004, 69, 5813. to be distinctly different from the analogous Pd-catalyzed reaction, and (d) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921. (e) Trost, B. M.; Van Vranken, in some cases, the levels of regio-, enantio-, and diastereoselectivity are D. L. Chem. Rev. 1996, 96, 395. (f) Trost, B. M. Acc. Chem. Res. 1996, 29, 355. (2)(a) Trost, B. M.; Bunt, R. C. J. Am. Chem. Soc. 1994, 116, 4089. (b) Ernst, M.; Helmchen, G. Synthesis enhanced relative to the palladium-catalyzed reaction. Trost and Dogra 2002, 1953. (c) Ernst, M.; Helmchen, G. Angew. Chem., Int. Ed. 2002, 41, 4054. (3) Trost, 9 Ligands Trost report the total synthesis of (–)-Δ -trans-tetrahydrocannabinol, a B. M. et al. J. Am. Chem. Soc. 1997, 119, 7879. (4)(a) Trost, B. M.; Toste, F. D. J. Am. Chem. psychomimetic of marijuana, utilizing a molybdenum catalyst.9 An Soc. 1999, 121, 3543. (b) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 2003, 125, 3090. overall yield of 30% of enantiomerically pure (–)-Δ9-trans-tetrahydro- (c) Trost, B. M.; Crawley, M. L. J. Am. Chem. Soc. 2002, 124, 9328. (d) Trost, B. M.; Crawley, cannabinol (Scheme 1). M. L. Chem.-Eur. J. 2004, 10, 2237. (5) Trost, B. M.; Kondo, Y. Tetrahedron Lett. 1991, 32, 1613. (6) Trost, B. M. et al. J. Am. Chem. Soc. 1996, 118, 6297. (7)(a) Trost, B. M.; Pulley, S. R. J. Am. Chem. Soc. 1995, 117, 10143. (b) Trost, B. M. et al. Chem.-Eur. J. 2001, 7, 1619. (8)(a) Trost, B. M.; Van Vranken, D. L. J. Am. Chem. Soc. 1993, 115, 444. (b) Trost, B. M. et al. J. Am. Chem. Soc. 1992, 114, 9327. (c) Trost, B. M.; Patterson, D. E. J. Org. Chem. 1998, 63, 1339. (9) Trost, B. M.; Dogra, K. Org. Lett. 2007, 9, 861.

OCH3 EE OCO2CH3 H CO 3 O E C5H11 OCH3 Na Mo(C H )(CO) (5 mol%) C H OCH E 7 8 3 5 11 3 C H OH (S,S)-DACH-pyridyl (7.5 mol %) 5 11 THF 95%, 94% ee

E = CO2CH3 Scheme 1

(R,R)-DACH-naphthyl Trost ligand, 95% 8 (S,S)-DACH-phenyl Trost ligand, 95% 8

O O O O P NH HN P P NH HN P

(1S,2S)-(–)-1,2‑Diaminocyclohexane-N,N′-bis(2‑diphenylphosphino- ‑ ′ ‑ (1R,2R)-(+)-1,2 Diaminocyclohexane-N,N -bis(2 diphenylphosphino- benzoyl) ‑ 1 naphthoyl) [169689‑05‑8] ‑ ‑ [174810 09 4] C44H40N2O2P2 C52H44N2O2P2 FW 690.75 FW 790.87 S: 36/37/39 692778-250MG 250 mg 692794-250MG 250 mg 692778-1G 1g 692794-1G 1g

(S,S)-DACH-Naphthyl Trost Ligand, 95% 8 (R,R)-DACH-pyridyl Trost ligand, 95% 8 (–)-N,N′-(1R,2R)-1,2-Diaminocyclohexanediylbis(2- pyridinecarboxamide) O O ‑ ‑ O O P NH HN P [218290 24 5] NH HN C18H20N4O2 FW 324.38 N N

692751-500MG 500 mg (1S,2S)-(–)-1,2‑Diaminocyclohexane-N,N′-bis(2‑diphenylphosphino- 692751-1G 1g 1‑naphthoyl) [205495‑66‑5] 8 C52H44N2O2P2 (S,S)-DACH-pyridyl Trost ligand, 95% FW 790.87 (1S,2S)-(+)-1,2-Bis[(2-pyridinylcarbonyl)amino]cyclo- 692786-250MG 250 mg hexane; (1S,2S)-N,N′-1,2-Cyclohexanediylbis(2-pyri- O O 692786-1G 1g dinecarboxamide); (1S,2S)-1,2-Bis(2- NH HN pyridinecarboxamido)cyclohexane; (+)-N,N′-(1S,2S)- N N (R,R)-DACH-phenyl Trost ligand, 95% 8 1,2-Diaminocyclohexanediylbis(2-pyridinecarboxamide) [172138‑95‑3] C18H20N4O2 O O FW 324.38 P NH HN P L R: 22-36/37/38 S: 26 692743-500MG 500 mg 692743-1G 1g (1R,2R)-(+)-1,2‑Diaminocyclohexane-N,N′-bis(2‑diphenylphosphino- benzoyl) [138517‑61‑0] C44H40N2O2P2 FW 690.75 692808-250MG 250 mg 692808-1G 1g

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Landis Ligands

The interest in asymmetric reactions has been growing for the past Asymmetric Allylic Alkylation 40 years. To address the challenges of synthesizing chiral building blocks with high yields and high selectivities, researchers developed a broad The asymmetric allylic alkylation reaction is an attractive reaction to form – range of catalysts. Two of the essential components for highly active and a new C C bond with a desired nucleophile enantioselectively. selective catalysts are the ligand and the metal. Professor Landis and Professor Landis and co-workers utilized this reaction to test newly ‑ 2 co-workers developed a series of new ligands based on chiral synthesized chiral 3,4 diazaphospholanes (Diazaphos-PPE). With the 3,4‑diazaphospholane structures (Figure 1). These ligands are highly presence of a palladium catalyst, these new ligands yielded outstanding active for enantioselective hydroformylation and enantioselective allylic conversions and enantioselectivities with a variety of substrates. Using ‑ ‑ ‑ alkylation reactions. These two transformations are essential to access a 1,3 diphenylallyl acetate and 2 penten-4 yl acetate as reactants, with variety of chiral blocks for the synthesis of more complex molecules. dimethyl malonate as the nucleophile, Clark and Landis demonstrated that Diazaphos-PPE is surpassing other ligands with high yields and selectivities for both substrates (Scheme 2).

Landis Ligands Synthesis of Isoxazolines and Imidazoles The asymmetric hydroformylation reaction is a highly chemoselective References: (1) Thomas et al. Org. Lett. 2007, 9, 2665. (2) Clark, T. P. ; Landis, C. R. J. Am. transformation allowing the conversion of terminal olefins into optically Chem. Soc. 2003, 125, 11792. active aldehydes. Despite the recognized powerful methodology of this transformation, it has been sporadically utilized on a commercial scale due to the low reaction rates, the challenges to control the region- and O R O RR O enantioselectivities simultaneously and the limited substrate scope. N N N PPh P P Professor Landis and coworkers developed a new family of ligands based N N ‑ N on 2,5 disubstituted phospholane addressing these issues. O O O O R R R Utilizing this newly developed ligand, Thomas and coworkers synthesized R: N a series of oxazolines and imidazoles.1 Reacting vinyl acetate with H Rh(CO)2(acac) and (R,R,R)or(S,S,S)-Diazaphos-SPE in a reactor with Diazaphos-PPE Diazaphos-SPE CO and H2 at 400 psi yielded the corresponding chiral aldehydes with 94% conversion and 96% ee (Scheme 1). It is important to note that a Figure 1 catalyst loading of only 0.001 mol% is necessary to complete this transformation. Following this reaction Thomas and coworkers ensured the conservation of the enantioselectivity by synthesizing the isoxazolines and imidazoles with overall good yields.

OH N Diazaphos-SPE (0.0012 mol %) CHO ∗∗ NH OH•HCl ∗∗ Rh(CO)2acac (0.001 mol %) 2 OAc H3C OAc H3C OAc pyridine CO/H2 (400 psi), THF (R) or (S) (R) or (S) 94% yield 96% ee

NCS NaOCl cat. NEt3 X O X OCOC6F5 OH OH O allylbenzyl- N NPh N C F COCl NPh N Cl N N 6 5 amine

H C OAc NEt3 H C OAc H3C OAc H C OAc 3 3 H3C OAc 3 Pd(PPh3)4 X = Ph, 64% NEt3 p-MeOPh, 65% CH3 4-pyridyl, 80% Ph NN

H3C OAc 63%

Scheme 1

O O η3 OAc ( -C3H5PdCl)2 (2 mol %) MeO OMe Diazaphos-PPE (4 mol %) ∗∗ R R R R CH (CO Me) , AgPF , R= Me, Ph 2 2 2 6 >95% yield CH2Cl2, NaOAc 91% ee

Scheme 2

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(S,S,S)-DiazaPhos-PPE 8 Bis[(S,S,S)-DiazaPhos-SPE] 8 2,2′-[(1S,3S)-2,3,5,10-Tetrahydro-5,10-dioxo-2- H O O phenyl-1H-[1,2,4]diazaphospholo[1,2-b]phthal- N azine-1,3-diyl]bis[N-(1S)-1-phenylethyl] NH HN O O CH 3 O O benzamide H3C CH3 N Ligands Landis [615538‑63‑1] P N N N P P N N C46H39N4O4P O CH FW 742.80 O 3 O O H3C CH3 N NH HN H O O

685240-100MG 100 mg 2,2′,2″,2′′′-(1,2‑Phenylenebis[(1S,3S)-tetrahydro-5,8‑dioxo-1H-[1,2,4] 685240-500MG 500 mg diazaphospholo[1,2-a]pyridazine-2,1,3(3H)-triyl])tetrakis(N-[(1S)- 1‑phenylethyl])benzamide 8 (R,R,S)-DiazaPhos-PPE [851770‑14‑4] 2,2′-[(1R,3R)-2,3,5,10-Tetrahydro-5,10-dioxo- C78H72N8O8P2 H FW 1311.40 2-phenyl-1H-[1,2,4]diazaphospholo[1,2-b] N phthalazine-1,3-diyl]bis[N-[(1S)-1-phenylethyl] 685259-100MG 100 mg O O CH3 benzamide] 685259-500MG 500 mg N [615257‑74‑4] P N C46H39N4O4P Bis[(R,R,S)-DiazaPhos-SPE] 8 FW 742.80 O O CH3 N H O O

NH HN O O 685089-100MG 100 mg H3C CH3 N N 685089-500MG 500 mg P P N N

O O H3C CH3 NH HN

O O

2,2′,2″,2′′′-(1,2‑Phenylenebis[(1R,3R)-tetrahydro-5,8‑dioxo-1H-[1,2,4] diazaphospholo[1,2-a]pyridazine-2,1,3(3H)-triyl])tetrakis(N-[(1S)- 1‑phenylethyl])benzamide [851609‑33‑1] C78H72N8O8P2 FW 1311.40 685232-100MG 100 mg 685232-500MG 500 mg

New Metal Precursors for Asymmetric Catalysis

Sigma-Aldrich® is pleased to offer a comprehensive portfolio of rhodium and iridium BARF complexes for asymmetric transformations.

F3C CF3 F3C CF3 F3C CF3 F C CF F C CF F C CF 3 3 Na 3 3 3 3 B Rh B Ir B

F3C CF3 F3C CF3 F3C CF3

Sodium tetrakis[3,5- Bis(1,5-cyclooctadiene)rhodium(I) Bis(cyclooctadiene)iridium(I) bis(trifl uoromethyl)phenyl]borate tetrakis[3,5-bis(trifl uoromethyl)- tetrakis(3,5-bis(trifl uoromethyl)- 692360 phenyl]borate phenyl)borate 692573 693774

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Tired of browsing through various catalogs and databases • 800+ Boronic Acids for the research products you need? Relax! and Derivatives • 200+ Pd Catalysts Sigma-Aldrich® introduces Chem Product Central™, featuring the industry-leading range of 40,000+ products including cutting-edge catalysts and ligands, novel and • 400+ Privileged Ligands classical synthetic reagents, and diverse libraries of building blocks. Chem Product • 5,000+ Heterocyclic Central™ uniquely categorized all chemical products by compound classes and Building Blocks application areas—making it easy to quickly ﬁ nd what you need. Regular updates ensure that you have the most innovative products for your research. and so much more!

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Aminophosphine Ligands

An increased interest in aminophosphine type ligands used for Ph asymmetric synthesis has been witnessed. This growth in popularity of NH2 PPh aminophosphine ligands in asymmetric synthesis is in part due to the Fe 2 O HO Ligands Aminophosphine growing number of convenient synthetic pathways leading to useful 1 ligand sets. Several groups have been using amino acids as precursors to [Ru(benzene)Cl2]2

synthesize these ligands. Researchers at Kanata have synthesized several H2, t-BuOK, i-PrOH sets of aminophosphine ligands showing great reactivity and selectivity in 100%, 66.7% ee a wide array of enantioselective reactions. Scheme 1 Ruthenium Hydrogenation Catalysts A growing area of application for aminophosphine ligands in 2 Ph2 Ph2 asymmetric synthesis is in ruthenium-catalyzed hydrogenations. This P Cl P process is integral in the preparation of alcohols and amines, which are Ru N Cl N essential in the pharmaceutical, agrochemical, material, and fine O H2 H2 chemicals industries. OH H2 / base Chen et al. have described the use of ferrocenylaminophosphines in the 2 ruthenium-catalyzed asymmetric hydrogenation of acetonaphthone. 100% cis Using precatalysts [RuCl2(benzene)]2 and the ferrocenyl based aminophosphine ligand, they found that the hydrogenation proceeded Scheme 2 quickly with reasonable enantioselectivity (Scheme 1). Abdur-Rashid et al. reported the synthesis of cis-2-tert-butylcyclohexyl alcohol using bis-2-(diphenylphosphino)ethylamine ruthenium dichloride as a catalyst.3 Excellent selectivities were reported yielding only the cis-product (Scheme 2).

References: (1)(a) Abdur-Rashid, K. et al. J. Am. Chem. Soc. 2002, 124, 15104. (b) Abdur- Rashid, K. et al. J. Am. Chem. Soc. 2001, 123, 7473. (c) Guo, R. et al. J. Am. Chem. Soc. 2005, 127, 516. (2) Chen, W.; Mbafor, W.; Roberts, S. M.; Whittall, J. Tetrahedron: Asymmetry 2006, 17,1161. (3) Abdur-Rashid, K. et al. Adv. Synth. Catal. 2005, 347, 571.

2-(Di-tert-butylphosphino)ethylamine 8 2-(2-(Diphenylphosphino)ethyl)pyridine

C10H24NP [10150‑27‑3] CH3 FW 189.28 H3C NH2 C19H18NP H3C P FW 291.33 N P

H3C CH3 CH3 JMR: 17-34 S: 26-36/37/39-45 695599-100MG 100 mg 697419-250MG 250 mg (1S,2S)-(2-Amino-1-phenylpropyl)diphenylphosphine 8 2-(Diisopropylphosphino)ethylamine 8 (1S,2S)-(2-Diphenylphosphino)-1-methyl-2-phenylethyl- C8H20NP CH3 amine FW 161.22 NH2 NH2 C21H22NP H3C P P FW 319.38 CH3 H3C CH3 L R: 36/37/38 S: 26 R: 36/37/38 S: 26 697427-250MG 250 mg L 697583-100MG 100 mg 2-(Diphenylphosphino)ethylamine, ≥95.0% (GC) (2-Aminoethyl)diphenylphosphine (1S,2S)-2-(Diphenylphosphino)-1,2-diphenylethyl- 8 [4848‑43‑5] amine C H NP 14 16 P C H NP FW 229.26 26 24 NH2 FW 381.45

NH2 P M R: 34 S: 26-36/37/39-45 43162-1G 1g L R: 36/37/38 S: 26 697389-100MG 100 mg

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(1S,2S)-(2-N-Methylamino-1-phenylpropyl)diphenyl- 8 (Rp)-1-[(1S)-(1-Aminoethyl)]-2-(diphenylphosphino) 8 phosphine ferrocene

(1S,2S)-N,1-Dimethyl-2-(diphenylphosphino)-2-phenyl- (Rp)-1-(1S)-[(2-Diphenylphosphino)-ferrocenyl]ethan- ethylamine amine C H NP CH3 ‑ ‑ P 22 24 [607389 84 4] NH2 P CH3 FW 333.41 N C24H24FeNP H CH3 FW 413.27 Fe

697397-100MG 100 mg 697354-100MG 100 mg

2-[(11bS)-3H-Binaphtho[2,1-c:1′,2′-e]phosphepin-4 8 Dichlorobis[2-(di-tert-butylphosphino)ethylamine]ruthe- (5H)-yl]ethanamine nium(II), 97%

C24H22NP C20H48Cl2N2P2Ru t-Bu t-Bu H2 FW 355.41 FW 550.53 P Cl N NH Ru P 2 N Cl P H2 t-Bu t-Bu L R: 36/37/38 S: 26 697370-100MG 100 mg Aminophosphine Ligands 664987-250MG 250 mg (1S,2S)-1-((4R,11bS)-3H-Binaphtho[2,-c:1′,2′-e]phos- 8 664987-1G 1g phepin-4(5H)-yl)-1-phenyl-2-propanamine Dichlorobis(2-(diphenylphosphino)ethylamine)ruthenium(II), C31H28NP 95% FW 445.53 H2N CH3 [506417‑41‑0] P Ph Ph H2 C28H32Cl2N2P2Ru P Cl N FW 630.49 Ru N Cl P H2 Ph Ph 697362-100MG 100 mg L R: 36/37/38 S: 26 ′ ′ 8 (1S,2S)-2-[(4R,11bS)-3H-dinaphtho[2,1-c:1 ,2 -e]phos- 664979-250MG 250 mg phepin-4(5H)-yl]-1,2-diphenylethylamine 664979-1G 1g C36H30NP H N FW 507.60 2 Chlorodihydrido[bis(2‑diisopropylphosphino)ethylamine]iri- P dium(III), mixture of isomers, 97%

C16H39ClIrNP2 H3C CH3 FW 535.11 CH P 3 R: 11-36/37/38 S: 26 Cl CH3 JL NH Ir H H 696943-100MG 100 mg P CH3 H3C CH3 CH3 L R: 36/37/38 S: 26 664995-250MG 250 mg 664995-1G 1g

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AD-mix-α and AD-mix-β are sold under license from Rhodia Pharma Solutions. Johnson Matthey — BoPhoz™ Air Products & Chemicals, Inc. — Selectfluor® Kanata Chemical Technologies, Inc. — Ferrocelane™, RajPhos™ DSM — MonoPhos™ Ferrocelane is sold in collaboration with Kanata Chemical Technologies, Inc. MonoPhos™ family ligands are sold under license from DSM for research purposes only. for research purposes only. Patent WO 0204466 applies. Nippon Chemical Industry Co., Ltd. — QuinoxP® Eppendorf-Netheler-Hinz GmbH — Eppendorf® Sigma-Aldrich Biotechnology LP and Sigma-Aldrich Co. — ProteoSilver™, Evonik Degussa GmbH — catASium® Sigma-Aldrich® catASium® is sold in collaboration with Evonik Degussa GmbH for research purposes. Solvias AG — Solvias® GE Healthcare — Sepharose® Takasago Intl. Corp. — SEGPHOS® Imperial Chemical Industries Ltd. — Coomassie® SEGPHOS® is sold in collaboration with Takasago for research purposes only.

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HPLC Chiral Column Screening Small-Scale Enantiomeric Purifi cation HPLC chiral column screening protocol includes 3 mobile phase Isolation of enantiomers is often required. The output of a small-scale conditions run using 6 different chiral stationary phases. Positive purifi cation project can be milligram to gram quantities, depending separation is verifi ed on a separate system. Enantiomers are on the needs of the client. Typical enantiomeric purity is 98% and identifi ed as (+) and (-) using the Chiralyser optical rotation verifi cation is determined by analytical methods established in the detection system. screening study.

GC Chiral Column Screening GC column screening involves exploration of 4 GC chiral phases. Samples that require derivatization are veriﬁ ed by GC-MS.

HPLC and GC Chiral Method Optimization and Development Services To establish the most efﬁ cient method, an optimization study can be conducted as an outcome of the initial column screening. Method optimization may vary, depending on the intended use of the method. Some typical uses include: • Isolation/puriﬁ cation of enantiomers • Resolution of metabolites • Establishment of minimum detection limits • LC-MS compatible methods for clinical, stability, or dissolution studies

Typical experiments in the optimization study include modifying buffer and pH, organic modiﬁ er type and strength, and column temperature.

Pricing, Turnaround Time and Deliverables HPLC and GC chiral column screening is typically completed within 3 working days. A full report is supplied and a column is recommended upon completion of the project. A charge for the service is incurred whether or not a separation is identiﬁ ed. At that time, optimization, method development, and puriﬁ cation studies can be initiated if desired by the client.

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Supelcoadsized_ed.indd 1 5/7/2008 8:47:23 AM COMBINATION OF PARTICULAR RISKS: Risk Phrases 14/15: Reacts violently with water, liberating extremely flammable gases INDICATION OF PARTICULAR RISKS: 15/29: Contact with water liberates toxic, extremely flammable gas R1: Explosive when dry 20/21: Harmful by inhalation and in contact with skin 2: Risk of explosion by shock, friction, fire or other sources of 20/21/22: Harmful by inhalation, in contact with skin and if swallowed ignition 20/22: Harmful by inhalation and if swallowed 3: Extreme risk of explosion by shock, friction, fire or other 21/22: Harmful in contact with skin and if swallowed sources of ignition 23/24: Toxic by inhalation and in contact with skin 4: Forms very sensitive explosive metallic compounds 23/24/25: Toxic by inhalation, in contact with skin and if swallowed 5: Heating may cause an explosion 23/25: Toxic by inhalation and if swallowed 6: Explosive with or without contact with air 24/25: Toxic in contact with skin and if swallowed 7: May cause fire 26/27: Very toxic by inhalation and in contact with skin 8: Contact with combustible material may cause fire 26/27/28: Very toxic by inhalation, in contact with skin and if swal-

Risk & Safety 9: Explosive when mixed with combustible material lowed 10: Flammable 26/28: Very toxic by inhalation and if swallowed 11: Highly flammable 27/28: Very toxic in contact with skin and if swallowed 12: Extremely flammable 36/37: Irritating to eyes and respiratory system 14: Reacts violently with water 36/37/38: Irritating to eyes, respiratory system and skin 15: Contact with water liberates extremely flammable gases 36/38: Irritating to eyes and skin 16: Explosive when mixed with oxidizing substances 37/38: Irritating to respiratory system and skin 17: Spontaneously flammable in air 39/23: Toxic: danger of very serious irreversible effects through inha- 18: In use may form flammable/explosive vapor-air mixture lation 19: May form explosive peroxides 39/23/24: Toxic: danger of very serious irreversible effects through inha- 20: Harmful by inhalation lation and in contact with skin 21: Harmful in contact with skin 39/23/24/25: Toxic: danger of very serious irreversible effects through inha- 22: Harmful if swallowed lation, in contact with skin and if swallowed 23: Toxic by inhalation 39/23/25: Toxic: danger of very serious irreversible effects through inha- 24: Toxic in contact with skin lation and if swallowed 25: Toxic if swallowed 39/24: Toxic: danger of very serious irreversible effects in contact 26: Very toxic by inhalation with skin 27: Very toxic in contact with skin 39/24/25: Toxic: danger of very serious irreversible effects in contact 28: Very toxic if swallowed with skin and if swallowed 29: Contact with water liberates toxic gas 39/25: Toxic: danger of very serious irreversible effects if swallowed 30: Can become highly flammable in use 39/26: Very toxic: danger of very serious irreversible effects through inhalation 31: Contact with acids liberates toxic gas 39/26/27: Very toxic: danger of very serious irreversible effects through 32: Contact with acids liberates very toxic gas inhalation and in contact with skin 33: Danger of cumulative effects 39/26/27/28: Very toxic: danger of very serious irreversible effects through 34: Causes burns inhalation, in contact with skin and if swallowed 35: Causes severe burns 39/26/28: Very toxic: danger of very serious irreversible effects through 36: Irritating to the eyes inhalation and if swallowed 37: Irritating to the respiratory system 39/27: Very toxic: danger of very serious irreversible effects in contact 38: Irritating to the skin with skin 39: Danger of very serious irreversible effects 39/27/28: Very toxic: danger of very serious irreversible effects in con- 40: Limited evidence of a carcinogenic effect tact with skin and if swallowed 41: Risk of serious damage to eyes 39/28: Very toxic: danger of very serious irreversible effects if swal- 42: May cause sensitization by inhalation lowed 43: May cause sensitization by skin contact 42/43: May cause sensitization by inhalation and skin contact 44: Risk of explosion if heated under confinement 48/20: Harmful: danger of serious damage to health by prolonged 45: May cause cancer exposure through inhalation 46: May cause heritable genetic damage 48/20/21: Harmful: danger of serious damage to health by prolonged 48: Danger of serious damage to health by prolonged exposure exposure through inhalation and in contact with skin 49: May cause cancer by inhalation 48/20/21/22: Harmful: danger of serious damage to health by prolonged 50: Very toxic to aquatic organisms exposure through inhalation, in contact with skin and if 51: Toxic to aquatic organisms swallowed 52: Harmful to aquatic organisms 48/20/22: Harmful: danger of serious damage to health by prolonged 53: May cause long-term adverse effects in the aquatic environ- exposure through inhalation and if swallowed ment 48/21: Harmful: danger of serious damage to health by prolonged 54: Toxic to flora exposure in contact with skin 55: Toxic to fauna 48/21/22: Harmful: danger of serious damage to health by prolonged exposure in contact with skin and if swallowed 56: Toxic to soil organisms 48/22: Harmful: danger of serious damage to health by prolonged 57: Toxic to bees exposure if swallowed 58: May cause long-term adverse effects in the environment 48/23: Toxic: danger of serious damage to health by prolonged 59: Dangerous for the ozone layer exposure through inhalation 60: May impair fertility 48/23/24: Toxic: danger of serious damage to health by prolonged 61: May cause harm to the unborn child exposure through inhalation and in contact with skin 62: Possible risk of impaired fertility 48/23/24/25: Toxic: danger of serious damage to health by prolonged 63: Possible risk of harm to the unborn child exposure through inhalation, in contact with skin and if 64: May cause harm to breast-fed babies swallowed 65: Harmful: may cause lung damage if swallowed 48/23/25: Toxic: danger of serious damage to health by prolonged 66: Repeated exposure may cause skin dryness or cracking exposure through inhalation and if swallowed 67: Vapors may cause drowsiness and dizziness 48/24: Toxic: danger of serious damage to health by prolonged 68: Possible risk of irreversible effects exposure in contact with skin 48/24/25: Toxic: danger of serious damage to health by prolonged exposure in contact with skin and if swallowed 48/25: Toxic: danger of serious damage to health by prolonged exposure if swallowed

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CFVol8No2FINAL.indd Sec1:90 5/15/2008 10:45:12 AM 50/53: Very toxic to aquatic organisms, may cause long-term 42: During fumigation/spraying wear suitable respiratory equip- adverse effects in the aquatic environment ment (appropriate wording to be specified by the manufac- 51/53: Toxic to aquatic organisms, may cause long-term adverse turer) effects in the aquatic environment 43: In case of fire, use ... (indicate in the space the precise type 52/53: Harmful to aquatic organisms, may cause long-term adverse of fire-fighting equipment. If water increases the risk add effects in the aquatic environment - Never use water) 68/20: Harmful: possible risk of irreversible effects through inhala- 45: In case of accident or if you feel unwell, seek medical advice Risk & Safety tion immediately (show label where possible) 68/20/21: Harmful: possible risk of irreversible effects through inhala- 46: If swallowed, seek medical advice immediately and show this tion and in contact with skin container or label 68/20/21/22: Harmful: possible risk of irreversible effects through inhala- 47: Keep at temperature not exceeding ... ºC (to be specified by tion, in contact with skin and if swallowed the manufacturer) 68/20/22: Harmful: possible risk of irreversible effects through inhala- 48: Keep wet with ... (appropriate material to be specified by tion and if swallowed the manufacturer) 68/22: Harmful: possible risk of irreversible effects if swallowed 49: Keep only in the original container 68/21: Harmful: possible risk of irreversible effects in contact with 50: Do not mix with ... (to be specified by the manufacturer) skin 51: Use only in well-ventilated areas 68/21/22: Harmful: possible risk of irreversible effects in contact with 52: Not recommended for interior use on large surface areas skin and if swallowed 53: Avoid exposure - obtain special instruction before use 56: Dispose of this material and its container to hazardous or Safety Phrases special waste collection point 57: Use appropriate container to avoid environ mental contami- INDICATION OF SAFETY PRECAUTIONS: nation S1: Keep locked up 59: Refer to manufacturer/supplier for information on recovery/ 2: Keep out of the reach of children recycling 3: Keep in a cool place 60: This material and/or its container must be disposed of as 4: Keep away from living quarters hazardous waste 5: Keep contents under ... (appropriate liquid to be specified 61: Avoid release to the environment. Refer to special instruc- by the manufacturer) tions/safety data sheet 6: Keep under ... (inert gas to be specified by the manufac- 62: If swallowed, do not induce vomiting: seek medical advice turer) immediately and show this container or label 7: Keep container tightly closed 63: In case of accident by inhalation, remove casualty to fresh air 8: Keep container dry and keep at rest 9: Keep container in a well-ventilated place 64: If swallowed, rinse mouth with water (only if the person is 12: Do not keep the container sealed conscious) 13: Keep away from food, drink and animal feeding stuffs COMBINATION OF SAFETY PRECAUTIONS: 14: Keep away from ... (incompatible materials to be indicated 1/2: Keep locked up and out of the reach of children by the manufacturer) 3/7: Keep container tightly closed in a cool place 15: Keep away from heat 3/9/14: Keep in a cool well-ventilated place away from ... (incompat- 16: Keep away from sources of ignition - No smoking ible materials to be indicated by manufacturer) 17: Keep away from combustible material 3/9/14/49: Keep only in the original container in a cool well-ventilated 18: Handle and open container with care place away from ... (incompatible materials to be indicated 20: When using, do not eat or drink by manufacturer) 21: When using, do not smoke 3/9/49: Keep only in the original container in a cool well-ventilated 22: Do not breathe dust place 23: Do not breathe gas/fumes/vapor/spray (appropriate wording 3/14: Keep in a cool place away from ... (incompatible materials to to be specified by the manufacturer) be indicated by the manufacturer) 24: Avoid contact with skin 7/8: Keep container tightly closed and dry 25: Avoid contact with eyes 7/9: Keep container tightly closed and in a well-ventilated place 26: In case of contact with eyes, rinse immediately with plenty 7/47: Keep container tightly closed and at a temperature not of water and seek medical advice exceeding ... ºC (to be specified by manufacturer) 27: Take off immediately all contaminated clothing 20/21: When using, do not eat, drink or smoke 28: After contact with skin, wash immediately with plenty of ... 24/25: Avoid contact with skin and eyes (to be specified by the manufacturer) 27/28: After contact with skin, take off immediately all contami- 29: Do not empty into drains nated clothing and wash immediately with plenty of ... (to 30: Never add water to this product be specified by the manufacturer) 33: Take precautionary measures against static discharges 29/35: Do not empty into drains, dispose of this material and its 35: This material and its container must be disposed of in a safe container in a safe way way 29/56: Do not empty into drains, dispose of this material and its 36: Wear suitable protective clothing container at hazardous or special waste-collection point 37: Wear suitable gloves 36/37: Wear suitable protective clothing and gloves 38: In case of insufficient ventilation, wear suitable respiratory 36/37/39: Wear suitable protective clothing, gloves and eye/face pro- equipment tection 39: Wear eye/face protection 36/39: Wear suitable protective clothing and eye/face protection 40: To clean the floor and all objects contaminated by this mate- 37/39: Wear suitable gloves and eye/face protection rial use ... (to be specified by the manufacturer) 47/49: Keep only in the original container at temperature not 41: In case of fire and/or explosion do not breathe fumes exceeding ... ºC (to be specified by manufacturer)

Pictograms Pictograms are based on widely accepted standards.

F T Xn G E H O J F+ K T+ L Xi M C I B Q N R R Explosive Oxidizing Highly Flammable Toxic or Harmful or Corrosive Biohazard Dangerous for the Radioactive or Extremely Very Toxic Irritant Environment Flammable

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