Technical Information

Index

1. Asymmetric Hydrogenation 1.2. Direct Reductive Amination

1.1. Classical Hydrogenation 1.3. RuCl2(diphosphine)(diamine) catalyzed Hydrogenation 1.1.1 Functionalized ketones a. Aryl alkyl ketones & Heteroaryl alkyl ketones a. -Ketoesters b. Aryl aryl ketones b. -Ketoesters c. Others c. -Ketoesters d. Dynamic Kinetic Resolution d. Hydroxyacetones & Amino ketones e. 1.3-Diketones 2. Asymmetric Isomerization f. Keto sufonates & Keto phosphonates g. Dynamic Kinetic Resolution 3. Monophosphine Ligands for Pd catalyzed Coupling Reactions 1.1.2. Imines 3.1. Buchwald-Hartwig Reaction 3.2. Suzuki-Miyaura Reaction 1.1.3 Olefins a. ,-Uunsaturated Carboxylic Acids 4. Other Reactions b. Itaconic acid delivatives 4.1. Cyanomethylation c. Allyl alcohols 4.2. Vinylation & Phenylation d. ,-Unsaturated lactones 4.3. Fluorination e. Diketene & Methylene--butyrolactone 4.4. Aza-Michael addition f. Dehydro amino acids 4.5. Asymmetric alcoholysis of azlactone g. Enamides 4.6. Cyclotrimerization of terminal alkynes h. Enamino esters 5. Publications

1. Asymmetric hydrogenation

1.1. Classical Hydrogenation 1.1.1. Functionalized Ketones a. -Ketoesters H O O 2 OH O Ru/ L* R1 OR2 R1 * OR2

1 R = alkyl, aryl, heteroaryl OH O OH O OH O OH O Cl Ph O Me * OMe Ph * OR2 * OEt * OMe

SEGPHOS : >99% ee SEGPHOS3) : 98% ee SEGPHOS2,3) : 98.5% ee SEGPHOS2,3) : 99.4% ee 1) 2,3) BINAP : >99% ee (R2 = Me, S/C = 10,000) (S/C = 20,000) TolBINAP : 97.4% ee TolBINAP3) : 87% ee TolBINAP2,3) : 95.9% ee 2 (R = Et, S/C = 1,000) (S/C = 1,000)

1) Noyori, R. J. Am. Chem. Soc. 1987, 109, 5856. 2) Saito, T. Adv. Synth. Catal. 2001, 343, 264. 3) Sumi, K.

Topics Organomet. Chem. 2004, 6, 63. 4) JP H6-65226A, 1994.

b. -Ketoesters Enantioselectivities depend on the additives3).

O H2 OH OR2 Ru/ L* OR2 R1 R1 * O O

R1 = alkyl, aryl, heteroaryl

OH OH OH OH OR OR OEt Ph OMe tBu * Ph * Ph * * O O O O 1,2) SEGPHOS : 98.6% ee (R = Et) BINAP3) : 89% ee SEGPHOS1,2) : 93.7% ee SEGPHOS1) : 95.9% ee TolBINAP2) : 84.0% ee (R = Me) (S/ C = 1,500)

BINAP1,2) : 90.0% ee (S/ C = 1,000)

1) Saito, T. Adv. Synth. Catal. 2001, 343, 264. 2) Sumi, K. Topics Organomet. Chem. 2004, 6, 63. 3) Mashima,

K. J. Org. Chem., 1994, 59, 3064.

Technical Information c. -Ketoesters

O O H2 OH + OR2 Ru/L* OR2 H R1 R1 * O * O O R1 R1 = alkyl, aryl

1) Saito, T. Adv. Synth. Catal. 2001, 343, 264. 2) Sumi, K. Topics Organomet. Chem. 2004, 6, 63. 3) Noyori,

R. Tetrahedron Lett., 1990, 31, 5509. d. Hydroxyacetones and Amino ketones H 2 OH O Ru/L* X X R R *

OH OH OH

OH NMe2 Me * Me * OH Ph * 3) 3) L* = SEGPHOS1): 98.5% ee BINAP : 98% ee BINAP : 96% ee MeO-BIPHEP : 96% ee BIPHEMP : 93% ee BINAP : 83% ee 2) (92% ee)

1) Saito, T. Adv. Synth. Catal. 2001, 343, 264. 2) Noyori, R. J. Am. Chem. Soc. 1987, 109, 5856. 3) Noyori, R.

J. Am. Chem. Soc. 1988, 110, 629. e. 1,3-Diketones

H O O 2 OH O OH OH Ru/(R)-BINAP + Me Ph Me Ph Me Ph 89%, 98% ee (ketol : diol = 98 : 2)

Kawano, H. J. Chem. Soc., Chem. Commun, 1988, 87.

H2 O O Ru/(R)-BINAP OH OH R1 R2 R1 R2

R1 = R2 = Me : 100% ee, 98% de1) R1 = Me, R2 = Ph : 94% ee, 88% de2)

1) Noyori, R. J. Am. Chem. Soc. 1988, 110, 629. 3) Kawano, H. J. Chem. Soc., Chem. Commun, 1988, 87.

Technical Information

f. Keto sulfonates & Keto phosphonates

H2 O Ru/(R)-BINAP OH SO3Na SO3Na R1 R1 * OH OH OH OH

SO3Na SO3Na Me SO3Na SO3Na Me n-C15H31 Ph 97% ee 96% ee Me 97% ee 96% ee

Noyori, R. Tetrahedron 1999, 55, 8769.

H O 2 OH Ru/(R)-BINAP P(O)(OMe)2 P(O)(OMe)2 R1 R1 *

Ex.) OH P(O)(OMe) Me 2 98% ee

Noyori, R. J. Am. Chem. Soc. 1995, 117, 2931.

g. Dynamic Kinetic Resolution

O O H2 HO O HO O Ru/L* OR OR + OR n n n anti syn OH O OH O OH O OEt OMe OEt

(R)-SEGPHOS (R)-BINAP1) (S)-BINAP2) (R)-BINAP2) anti/syn 99/1 99/1 95/5 93/7 % ee 99.4 95 90 93

1) Mashima, K. J. Org. Chem., 1994, 159, 3064. 2) Noyori, R. Tetrahedron: Asymmetry, 1990, 31, 1159.

O OH O H2 O Ru/L* Me X Me X

X = NBn X = O DTBM-SEGPHOS1) : 98% ee, 98% de DTBM-SEGPHOS : 99% ee, 99% de 2) 3) TolBINAP : 88% ee, 99% de BINAP : 97% ee, 98% de

1) Sumi, K. Topics Organomet. Chem. 2004, 6, 63. 2) JPH10-204058. 3) Mashima, K. J. Org. Chem., 1994, 159,

3064.

Technical Information

O O H2 OH O Ru/L* R1 OR2 R1 OR2 X X

OH O OH O OH O

Me OMe Me OMe CH3(CH2)14 OMe Cl NHCOCH3 NHCOCH3

SEGPHOS DTBM-SEGPHOS DM-SEGPHOS >99% ee, 97% de 99% ee, 98% de 98% ee, 97.5% de

Sumi, K. Topics Organomet. Chem. 2004, 6, 63.

O H2 OH P(O)(OR2) Ru/L* P(O)(OR2) R1 2 R1 2 X X Ex.) OH P(O)(OMe) Me 2 Br L* = BINAP 84%, 98% ee

Noyori, R. J. Am. Chem. Soc. 1995, 117, 2931.

O O H2 OH O Ru/L* Me OMe Me OMe CH2Cl2 NHCOPh NHCOPh

BINAP : 90% ee, 74% de SEGPHOS : 80% de XylBINAP : 95% ee, 99% de DM-SEGPHOS : 98% ee, 94% de DT-BINAP : 99% ee, 98% de DTBM-SEGPHOS* : 99% ee, 99% de t (DT = 3,5-di- Bu)

*CH2Cl2/MeOH (7/1) was used as solvent.

Saito, T. Adv. Synth. Catal. 2001, 343, 264.

1.1.2. Imines

R3 H2 R3 N Mt/L* NH NH NH NH R1 R2 R1 * R2 Ph Ph Ph

Ru-(R)-TolBINAP1) Ir-(S)-BINAP2) Ir-(S)-BINAP3)

88.9% ee 85% ee 91% ee

1) JP 2005-281144A, 2005. 2) JP 2004-256460A, 2004. 3) WO 2006/022020 A1, 2006.

Technical Information

1.1.3. Olefins a. ,-Unsaturated carboxylic acids H 2 Me Ru/ L* R CO H R CO2H * 2

Me Me

CO2H CO2H MeO

(S)-BINAP1); 97% ee (S)-H8-BINAP2,3); 92% ee (S/C = 5,000)

1) Noyori, R. J. Org. Chem. 1987, 52, 3174. 2) Takaya, H. Synlett 1994, 501. 3) Takaya, H. J. Org. Chem. 1996,

61, 5510.

O H2 O Ru-L* 1 * R1 OH R OH 2 R2 R

O O O O * Me * OH * * Et OH Ph OH n-C3H7 OH Me Me Me Et

(S)-H8-BINAP: 97% ee (S) (S)-H8-BINAP: 96% ee (S) (S)-H8-BINAP: 89% ee (S) (S)-H8-BINAP: 95% ee (S) R ( )-BINAP: 96% ee (R) (R)-BINAP: 84% ee (R) (R)-BINAP: 30% ee (R) (R)-BINAP: 88% ee (R) 1) Zhang, X. Synlett 1994, 501. 2) Uemura, T. J. Org. Chem. 1996, 61, 5510. 3) Kumobayashi, H. Synlett 2001,

1055.

b. Itaconic acid delivatives

H R 2 R Ph Ru/ L* Me CO H CO2H 2 CO H CO H HO2C HO2C * 2 2 HO2C * HO2C * BINAP BINAP

88% ee 90% ee

1) Ikariya, T. J. Chem. Soc., Chem. Commn. 1985, 922. 2) Kumobayashi, H. J. Chem. Soc., Perkin Trans. I 1989,

1571. 3) Kumobayashi, H. Tetrahedron, Lett., 1987, 28, 1905. 4) Uchida, Y. J. Chem. Soc., Perkin Trans. I 1990,

1441.

Technical Information c. Allyl alcohols

H2 Me Me Me Me Ru/ (S)-BINAP Me OH Me OH 99% ee

Ru/ (R)-BINAP

H2 Me Me Me Me Ru/ (S)-BINAP Me Me OH OH 98% ee

Takaya, H. J. Am. Chem. Soc. 1987, 109, 1596.

d. ,-Unsaturated lactones & ketones

H O 2 O O H2 O Ru/ (S)-BINAP Ru/ (R)-BINAP O Me O Bu Bu

95% ee 98% ee

1) Ohta, T. J. Org. Chem. 1995, 60, 357. 2) Ohta, T. Tetrahedron Lett., 1992, 33, 635.

e. Diketene & Methylene--butyrolactone H H 2 Me 2 Ru/ L* Ru/ (S)-BINAP Me O O O O O O O O

1) 94% ee3) (S)-SEGPHOS 94% ee (S/C = 12,270) (S)-BINAP2) 92% ee (S/ C = 1,000) 1) US 006043380A, 1999. 2) Takaya, H. J. Chem. Soc. Chem. Commun. 1992. 3) Ohta, T. J. Org. Chem. 1995,

60, 357. f. Enamide

H2 MeO R Ru/ L* R MeO N 2 * N 2 N R R MeO COCH3 NH 1 OMe R R1 MeO Me R1 = H, aryl 2 OMe R = CHO, Me (S)-BINAP (S)-BINAP 99.5% ee 96% ee 1) Takaya, H. J. Am. Chem. Soc. 1986, 108, 7117.

Technical Information

g. Dehydro amino acids

H2 CO2H CO H 2 Mt/ L* CO2H * * Ph NHCOCH3 R NHCOCH 3 R NHCOCH3 Ru/ (S)-BINAP1,2); 92% ee (S) 3) Rh/ (S)-BINAP ; 84% ee (R)

1) Ikariya, T. J. Chem. Soc., Chem. Commn. I 1985, 922. 2) J. Chem. Soc., Perkin Trans. I 1989, 1571. 3)

Noyori, R. J. Am. Chem. Soc. 1980, 102, 7932.

h. Enamino esters R2 H R2 NH O 2 NH O Ru/ L* 1 3 1 3 R OR R * OR 2 R = H, aryl Cl Cl

NH2 O NH O Cl NH O Me * OMe * OMe * OMe DM-SEGPHOS SEGPHOS SEGPHOS 94.4 % ee 87.8% ee 88.4% ee 1) US 2004/0023344 A1, 2003. 2) US 2006/122225 A1, 2006.

1.2. Direct Reductive Amination of -ketoesters

H2 Ru/DM-SEGPHOS O O AcOH·H2N O AcONH4, AcOH R OMe R * OMe R = alkyl, aryl, heteroaryl - Product List as AcOH salt -

H2N O H2N O H2N O Me NH2 O Me OMe Et OMe i-Pr OMe Me OMe 92.9% ee 98% ee 99% ee 98% ee

NH2 O NH2 O anti/ syn = 86/ 14 OMe OMe 99% ee (anti) OBn 95% ee (syn) 99% ee 1) WO 2005/028419 A3, 2004. 2) Acc. Chem. Res.; 2007,40, 1385.

Technical Information

1.3. RuCl2(diphosphine)(diamine) catalyzed hydrogenation a. Aryl alkyl ketones & heteroaryl alkyl ketones

H O 2 OH Ru-L*/diamine 1 2 1 2 R R R * R R1 = aryl, heteroaryl 2 R = alkyl

OH OH R = R = H: 99% ee R Et: 99% ee R * * 2-Cl: % ee cyclo-C3H5: 99.7% ee 4-OMe: > 99.9% ee CF3: 96% ee 4-CF3: 99.6% ee (S)-XylBINAP/ (S)-DAIPEN

OH OH OH OH OH N S O Me N Me Me S Me Me

96% ee 99.6% ee 99% ee 99.7% ee 99% ee

(R)-XylBINAP/ (R)-DAIPEN

1) Noyori, R. J. Am. Chem. Soc. 1998, 120, 13529. 2) Noyori, R. Org. Lett. 2000, 2, 1749. b. Aryl aryl ketones R OH R O H2 Ru-L*/diamine *

(S)-XylBINAP/ (S)-DAIPEN

OH Cl OH Br OH CH3 Br OH

CH3 97% ee 96% ee 93% ee 98% ee Noyori, R. Org. Lett., 2000, 2, 659. c. Others OH OH OH Me Me * N

2) 97% ee >99% ee DM-SEGPHOS/ DAIPEN ; 90.5% ee 2) 74.5% ee 1) XylBINAP/ DAIPEN ; (S)-XylBINAP/ (S)-DAIPEN

1) Noyori, R. J. Am. Chem. Soc. 1998, 120, 13529. 2) US 2006041722, 2006.

Technical Information

d. Dynamic Kinetic Resolution

OH O H2 R Ru-L*/DPEN R

OH OH OMe

99% ee 93% ee 99% de 99.6% de (S)-XylBINAP/ (S)-XylBINAP/ (S,S)-DPEN (S,S)-DPEN

1) Matsumoto, T. Tetrahedron Lett. 1999, 40, 5043. 2) Noyori, R. J. Org. Chem. 1996, 61, 4872.

2. Asymmetric Isomerization 2 R R2 2 Rh/ L* H2O R 1 3 CHO R NR 2 1 3 1 R * NR 2 H+ R * L*; BINAP or TolBINAP

Me Me Me MeO CHO CHO CHO * * Ph * > 98% ee > 98% ee 95% ee (S/C = 400,000)

in l-Menthol process

Akutagawa, S. Tetrahedron Lett. 1985, 26, 5153.

3. Monophosphine Ligands for Pd Catalyzed Coupling Reactions

3.1. Buchwald-Hartwig Reaction

Suzuki, K.; Hori, Y.; Nishikawa, T.; Kobayashi, T. Adv. Synth. Catal. 2007, 349, 2089.

Technical Information

3.2. Suzuki-Miyaura Reaction

Suzuki, K.; Hori, Y.; Kobayashi, T. Synlett. 2007 20, 3206.

4. Other Reactions

4.1. Cyanomethylation

CuOtBu (10 mol%) O L* (15 mol%) OH + MeCN CN R H R *

R = n-Hex L* = (R)-DTBM-SEGPHOS : 84%, 58% ee MeO PAr (R)-DTBM-SEGPHOS (at rt) : 72%, 74% ee 2 (S)-TolBINAP : 21%, 16% ee MeO PAr2 (R,R)-Ph-BPE : 32%, 0% ee (R,S)-Josiphos : 18%, 6% ee (R)-SEGPHOS : 18%, 8% ee (R)-Tuned-BIPHEP (R)-Tuned-BIPHEP : 40%, 75% ee i i Ar = 4- PrO-3,5-( Pr)2-C6H2 Shibasaki, M. Org. Lett. 2005, 7, 3757.

4.2. Vinylation & Phenylation

1. CuF ·2H O (10 mol%) 3 2 2 O R L* (20 mol%) OH + Si(OMe) * 1 2 2 R1 R2 R R Y 2. TBAF R3

OH OH HO CO2Me Ph * Cl L* = (R)-DTBM-SEGPHOS : 99%, 94% ee* (R)-DTBM-SEGPHOS DTBM-SEGPHOS (R)-TolBINAP : 47%, 61% ee 92% ee 76%, 84% ee (R,R)-CHIRAPHOS : 24%, 7% ee (R,R)-Et-DuPHOS : 51%, 38% ee (S,S)-i-Pr-DuPHOS : 87%, 64% ee

* CuF2·2H2O (3 mol%), DTBM-SEGPHOS (6 mol%)

Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 4138.

Technical Information

4.3. Fluorination

O Pd/DTBM-SEGPHOS O NFSI t CO tBu CO Bu X = O, NH, NR X 2 X * 2 F n = 1, 2 n n

O O O O t t t t CO2 Bu CO2 Bu CO2 Bu CO2 Bu HN * O * BnN * * F F F F 1) 2) 2) 2) 93%, 92%ee 74%, 97%ee 89%, 98%ee 74%, 94%ee

1) Sodeoka, M. J. Am. Chem. Soc. 2002, 124, 14530. 2) Sodeoka, M. J. Org. Chem. 2007, 72, 246.

4.4. Aza-Michael addition NH ·TfOH MeO 2 [Pd(-OH){(S)-binap}]2(OTf)2 (0.2 mol%) MeO + O O NH O O Me N Me N O O 98%, 96% ee Sodeoka, M. Org. Lett. 2004, 6, 1861.

4.5. Asymmetric alcoholysis of azlactones O O Cu/(R)-DTBM-SEGPHOS O O O O MeO(CH ) OH MeO 2 2 MeO MeO O(CH ) OMe O O + 2 2 N 57% conv. N NH Ph Ph O Ph 99% ee 74% ee Tokunaga, M. J. Am. Chem. Soc. 2006, 128, 4481.

4.6. Cyclotrimerization of terminal alkynes R R R Rh/ (R)-DTBM-SEGPHOS 3 R + 91% R R R = C H 10 21 R 83 : 17 1) Tanaka, K. Org. Lett. 2003, 5, 4697. 2) Tanaka, K. Chem. Eur. J. 2005, 11, 1145.

Technical Information

5. Publications

(1) “Asymmetric synthesis by metal BINAP catalysts” Akutagawa, S. Applied Catalysis A: General 1995, 128, 171–207. doi: 10.1016/0926-860X(95)00097-6

(2) “Industrial application of asymmetric reactions catalyzed by BINAP-metal complexes” Kumobayashi, H. Recl. Trav. Chim. Pays-Bas 1996, 115, 201–210. doi: 10.1002/recl.19961150403

(3) “Rhodium/Ruthenium Applications” Sumi, K; Kumobayashi, H. In Organometallics in Process Chemistry (Topics in Organometallic Chemistry. Vol 6), Ed.; Larsen, R. D., Eds., Springer: Berlin, 2004; p. 63-95. doi: 10.1007/b11768

(4) “Recent advances in biaryl-type bisphosphine ligands” Shimizu, H.; Nagasaki, I.; Saito, T. Tetrahedron 2005, 61 (23), 5405-5432. doi: 10.1016/j.tet.2005.03.022

(5) “Developments in Asymmetric Hydrogenation from an Industrial Perspective” Shimizu, H.; Nagasaki, I.; Matsumura, K.; Sayo, N.; Saito, T. Acc. Chem. Res. 2007, 40, 1385-1393. doi: 10.1021/ar700101x

(6) “Chiral Ligands & Their Complexes” Kuriyama, W.; Sayo, N.; Saito, T. The Strem Chemiker 2007, 23, 1. http://www.strem.com/uploads/resources/documents/chemiker23.pdf

(7) “Axial Chiral Diphosphines: Atropisomeric Biaryl Diphosphine Ligands” Shimizu, H.; Nagasaki, I.; Sayo, N.; Saito, T. In Phosphorus Ligands in Asymmetric Catalysis: Synthesis and Applications. Ed. Bόrner,A. Eds.; Wiley-VCH: Weinheim, 2008, Vol. 1, p. 207. ChemInform, 2009, 40(43), nopage. doi: 10.1002/chin.200942246

Technical Information

(8) “(R)- and(S)-(4,4’-bi-1,3-benzodioxol)- 5,5’-diyl-bis(bis 3,5-di-tert–butyl-4-methoxyphenyl)phosphin” Saito, T. In e-EROS Encyclopedia of Reagents for Organic Synthesis, 2009 (accessed 27 March 2009). doi: 10.1002/047084289X.rn00766

(9) ”Eliminating Barriers in Large-Scale Asymmetric Synthesis.” Shimizu, H.; Sayo, N.; Saito, T. In Asymmetric Catalysis on Industrial Scale. 2nd Ed; Blaser, H.-U.; Federsel, H.-J. Eds.; Wiley-VCH: Weinheim, 2010, Chapter 12; p. 207– 218. doi: 10.1002/9783527630639.ch12

(10) “Industrial Application of the Asymmetric Reduction of C=O and C=N Bonds, including Enamides and Enamines” Shimizu, H.; S. Komiya; Nagasaki, I. In Comprehensive Chirality. Ed. Yamamoto,H.; Carreira, E. Eds.; Elsevier: Oxford, 9, 2012, 83–103. doi: 10.1016/B978-0-08-095167-6.00905-8

(11) “Development of New Phosphine Ligands (BRIDPs) for Efficient Palladium- Catalyzed Coupling Reactions and Their Application to Industrial Processes” Suzuki, K.; Hori. Y.; Nakayama,Y.; Kobayashi, T. J. Synth. Org. Chem., Jpn. 2011, 69, 1231. doi: 10.5059/yukigoseikyokaishi.69.1231

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