Josiphos (in progress)

Josiphosligands7

Palladium

Pd – Allylic alkylation JACS94-116-4062

PP-Josiphos_JACS94-116-4062_C

Orgmet04-23-2362. Reaction repeated under almost exactly the same conditions with (R,Sp)-Josiphos-1 to give S product 92% ee, 98% yield. JC08-254-79. For this reaction use of a heterogeneous catalyst derived from 5 wt% Pd/Al2O3 (1.4 mol% Pd) and R,Sp-Josiphos-1 (0.23 mol%) resulted in (S)-product of 88% ee (19% conversion) in THF at 60 oC for 24 h (substrate concentration = 0.18 M). Homogeneous Pd catalysis with R,Sp-Josiphos-1 in THF gave 92% ee (S).  With 8 mol% (R,Sp)-Josiphos-1 and 2 mol% [Pd(η3-C3H5)Cl]2 in THF heated at reflux a 84% ee (S), 86% yield was obtained with CH2(CO2Me)2 (2 eq.) and ZnEt2 (2 eq.) (i.e. via zinc enolate) See Tet06-62-1756.

Pd – Allylic phosphination Angew08-47-4878

PP-Josiphos_Angew08-47-4878

Pd – Allylic phosphonation EJOC14-6846

PP-Josiphos_EJOC14-6846

Absolute configuration not stated so assigned by comparison to JACS94-116-4062. For this reaction under the same conditions an ee of 97% (yield 95%) was achieved with (R)-BINAP. Reaction further exemplified using this ligand.

Pd – Hydrophosphorylation OL06-8-2099

PP-Josiphos_OL06-8-2099

The absolute configuration of the products was not established. No mention of exo/endo so presumably completely selective for the former.

Pd – Cross-coupling Orgmet09-28-152

PP-Josiphos_Orgmet09-28-152

Pd – Cross-coupling/C-H activation JACS12-134-7305

PP-Josiphos_JACS12-134-7305

Pd – Carbonyl alpha-arylation Orgmet11-30-6323

PP-Josiphos_Orgmet11-30-6323

Pd – Heck JOMC06-691-2159

PP-Josiphos_JOMC06-691-2159

The absolute configuration of the product was not established. Relative configuration confirmed by X-ray crystallography.

Pd – Hydrogenation CC11-47-5052

PP-Josiphos_CC11-47-5052

Hydrogenation proceeds following in situ tautomerisation to the corresponding cyclic N-sulfonylimine. Where R1 = alkyl <80% ee obtained, but with these substrates >90% ee was achieved with a Walphos ligand.

Pd – Reductive amination CC17-53-1704

PP-Josiphos_CC17-53-1704

Pd – Methoxycarbonylation Helv06-89-1610

PP-Josiphos_Helv06-89-1610

Pd – Desymmetrisation JACS04-126-10248

PP-Josiphos_JACS04-126-10248

Ruthenium

Ru – Hydrogenation Chirality00-12-514

PP-Josiphos_Chirality00-12-514

The catalyst formed in this way (and presumably used in the hydrogenation reaction) contained 10% of an unidentified compound. The corresponding catalyst derived from (R)-BINAP gave 99.9% ee (R selectivity) and 100% conversion for the same reaction under the same conditions.

OL09-11-907

PP-Josiphos_OL09-11-907

Ru – Transfer Hydrogenation Orgmet05-24-1660

PP-Josiphos_Orgmet05-24-1660

Angew07-46-7651

PP-Josiphos_Angew07-46-7651

It is noted that “much the same” enantioselectivity was observed with an in situ generated catalyst. Similar enantioselectivities observed where the catalyst used (following isolation) was derived from: i) replacement of Me attached to the aminopyridine stereogenic centre  by Ph or t-Bu and/or ii) use of Josiphos-6 instead of Josiphos-1.

CEJ08-14-9148

PP-Josiphos_CEJ08-14-9148

Orgmet10-29-3563

PP-Josiphos_Orgmet10-29-3563_1

Catalyst also generated in situ to give similar enantioselectivity and activity (generally with a catalyst loading of 0.01 mol%).

Osmium

Os – Transfer Hydrogenation Angew08-47-4362

PP-Josiphos_Angew08-47-4362_1

Orgmet10-29-3563

PP-Josiphos_Orgmet10-29-3563_Os

Catalyst also generated in situ to give similar enantioselectivity and activity (generally with a catalyst loading of 0.01 mol%).

Os – Hydrogenation Angew08-47-4362

PP-Josiphos_Angew08-47-4362_B
Rhodium

Rh – Hydrogenation JACS94-116-4062

PP-Josiphos_JACS94-116-4062

ASC08-350-898. The hydrogenation of methyl Z-α-acetamidocinnamate (MAC i.e. the first substrate above) results in a decrease in ee with an increase in hydrogen pressure. Orgmet07-26-3530. Hydrogenation of MAC (94% ee, 100% conversion) and dimethylitaconate (DMI – 99.5% ee, 100% conversion) under similar conditions (0.5 mol% Rh(NBD)2BF4, 0.525 mol% (R,Sp)-Josiphos-1, MeOH (substrate concentration = 0.25 M), H2 (1 bar) 25 oC, 1h). Product configurations are opposite to those given above. With (R,Sp)-Josiphos-5  DMI gave 92% ee, 96% conversion under these conditions. ASC06-348-1605. (R,Sp)-Josiphos-1/Rh(cod)2BF4 supported on alumina (CATAXA) with a phosphotungstic acid linker has been used for the hydrogention (160 bar) of DMI using continuous flow supercritical carbon dioxide as the reaction medium (83% ee, 24% conversion 55 oC). The absolute configuration of the product given in the graphical abstract (the only place where stated) is S, i.e. not R as given above. EJOC05-1909. Cat. From 1 mol% (R,Sp)-Josiphos-1 and 1 mol% Rh(cod)2BF4. Using this DMI (MeOH, substrate concentration = 0.21 M, H2 = 1.2 bar, 4 h, 70 oC) gave (S)-product in 99% ee, 100% conversion. Product configuration opposite to above scheme. Using MAC (MeOH, 0.21 M, H2 = 2.4 bar, 4 h, 110 oC) gave (S)-product in 74% ee, 100% conversion. Orgmet02-21-1766. Cat. From 0.5 mol% (R,Sp)-Josiphos-1 and 0.5 mol% Rh(NBD)2BF4. Using this DMI (MeOH, substrate concentration = 0.25 M, H2 = 1 bar, 22 h, 18 oC) gave (S)-product in 98.5% ee, 100% conversion. Product configuration opposite to above scheme. Using MAC (MeOH, 0.25 M, H2 = 1 bar, 66 h, 18 oC) gave (S)-product in 84.4% ee, 100% conversion.

ASC01-343-68

PP-Josiphos_ASC01-343-68

With 1 mol% catalyst loading also applied to  corresponding p-Me (97% ee, 100% conversion, 21 h) and p-CF3 (93% ee, 98% conversion, 18 h) substrates. The reaction is sensitive to the identity of the p-substituent (e.g. 30% ee with p-Cl).

ASC04-346-1481

PP-Josiphos_ASC04-346-1481

Absolute  configuration not stated so assigned by comparison to the result in JACS94-116-4062. With the [omin]BF4/H2O mixture (substrate 0.25 M wrt H2O and approx. 1:1 ratio by volume of ionic liquid/water) the catalyst (following decantation of aqueous phase) was reused six times with a 70% conversion from the final run. Essentially identical results reported with this substrate in ASC07-349-1803 (TBME 99% ee, tolene 98% ee, i-PrOH 97% ee – and as a 1:1 mixture with 1:1 [bmim]BF4).

ASC07-349-1803

PP-Josiphos_ASC07-349-1803

Absolute  configuration not stated so assigned by comparison to the result in JACS94-116-4062. Use of (R,Sp)-Josiphos-7 in i-PrOH also gave 99% ee, 100% conversion. Essentially identical ees were obtained when both ligands (and both solvents for 1) were used with 1:1 [bmim]BF4.

TA06-17-481

PP-JosiPhos_TA06-17-481

A dynamic kinetic resolution. Other Ar substituents gave <80% ee.

Synlett08-1532

PP-Josiphos_Synlett08-1532

ASC09-351-1423

PP-JosiPhos_ASC09-351-1423

Absolute configuration assigned by comparison to data in CEJ09-15-10983. Mandyphos-2 has also been applied to this reaction.

TA09-20-1437

PP-JosiPhos_TA09-20-1437

Absolute configuration assigned tentatively as S. Some of these results also reported in Orgmet09-28-888.

Tet09-65-8987

PP-Josiphos_Tet09-65-8987

Result from a ligand scoping study from which the best results were obtained with a Walphos ligand.

CC12-48-11978

PP-Josiphos_CC12-48-11978

Opposite (R) configured product obtained with (R,SP)-Josiphos-1 (76% ee). Higher ee values obtained with (R,R)-EtDuPHOS [(S)-product)] and a Taniaphos type ligand [(R)-product with further reduction to a 2-piperidinone, 98% ee].

OL15-17-1842

PP-Josiphos_OL15_17_1842

Rh – Isomerisation Helv01-84-230

PP-Josiphos_Helv01-84-230

Under the same conditions the corresponding E configured substrate gives the S product in 92% ee and 99% yield.

Rh – Hydroboration JACS94-116-4062

PP-Josiphos_JACS94-116_4062_B

Less than 1% of regioisomeric 2-phenylethanol formed. Relatively low reactivity in comparison to bis(diphenylphosphino) ligands due to the higher basicity of Josiphos-1.

JACS04-126-9200

PP-Josiphos_JACS04-126-9200Use of HBpin gives opposite enantioselection to that obtained with catacol borane (HBcat). HBPin is more stable and easier to use than HBcat, but obtaining the branched isomer is more challenging with the latter reagent.

 

Rh – Diazabicycle desymmetrisation Angew08-47-2085

PP-Josiphos_Angew08-47-2085

 

Rh – Asymmetric ring-opening JACS00-122-5650

PP-Josiphos_JACS00-122-5650

The reactions with MeOH, EtOH and i-PrOH were with 10 eq. of the alcohol and 1 mol% of the rhodium catalyst, but there is nothing to indicate they could not be carried out with the lower catalyst loading indicated. The actual catalyst loadings used (from SI) are variable (see representative example). There is significant confusion in both the paper and the SI of the correlation between the catalyst and product configurations. There are assigned using later papers from this group. The nitrogen example is the only example where the ee is >80% (others 45-74% ee). For MeOH an ee of 88% is reported in PNAS04-101-5455 with use of Josiphos-1 (compared to 96% with Josiphos-3), this paper also describes a mechanistic model. For MeOH/Josiphos-1 an ee of 92.4% (36% yield) was obtained by another group – see JOMC05-690-1166 (0.5 mol% [Rh(cod)Cl]2, 1 mol% ligand, 7 eq. MeOH, THF (substrate concentration 2.3 M), reaction heated [presumably reflux?] 5 h).

OL00-2-1677

PP-Josiphos_OL00-2-1677

More acidic phenols observed to add faster.

JACS01-123-7170

PP-Josiphos_JACS01-123-7170_1

Just (S,Rp)-Josiphos-3 and [Rh(cod)Cl]2 used for the calculation of ACE. Following the combination of these the catalyst was generated in situ by chloride to iodide ligand exchanges using AgOTf then Bu4NI. Reactions quantities and results given are taken from the SI which differ a little from the results presented in the paper (e.g. concentration = 1.0 M from SI but 0.2 M in paper). No preactivation by deprotonation of the malonates is required. Also given, with oxabenzonorbornadiene as the substate, are results with p-methoxybenzylamine (81% ee, 71% yield) and dibenzylamine (88% ee, 91% yield), although the exact conditions used is not entirely clear.

Tet01-57-5067

PP-Josiphos_Tet01-57-5067

Just (S,Rp)-Josiphos-3 and [Rh(cod)Cl]2 used for the calculation of ACE. Following the combination of these the catalyst was generated in situ by chloride to iodide ligand exchanges using AgOTf then Bu4NI.

OL02-4-3465

PP-Josiphos_OL02-4-3465

Just one example with Josiphos-3 which is incorrectly given in the paper as the (R,Sp)-enantiomer (i.e. correct in the abstact above). Reaction further exemplified (also with pyrrolidine, piperidine, morpholine and dibenzylamine as the nucleophile) using as ligand (S,S,Rp,Rp)-2,2′-bis(α-N,N-dimethylaminoethyl)-1,1′-bis(diphenylphosphino)ferrocene (a type of Ferriphos ligand that is not commercially available). In the paper this is incorrectly drawn as the (R,R,Sp,Sp)-enantiomer. For more details see JACS06-128-6837.

Rh – Asymmetric ring-opening (+isomerisation and oxidation) Angew11-50-7346

PP-Josiphos_Angew11_50_7346

Rh – Epoxide isomerisation Angew17-56-6307

PP-Josiphos_Angew17

Rh – Hydroamination of allenes CS16-7-3313

PP-Josiphos_CS16-7-3313

 

Rh – Conjugate addition EJOC02-3552

PP-Josiphos_EJOC02-3552

Conditions stated are the optimised conditions with which the reaction was exemplified with (R)-BINAP (16 examples). For this example (S,Rp)-Josiphos-1 gave the same ee (and configuration) and the implication is these conditions were also used. Water is crucial for the reaction as in its absence the reaction is very slow and the ee significantly reduced.

Iridium

Ir – Hydrogenation

JOMC01-621-34_Chimia99-53-275

PP-Josiphos_JOMC01-621-34_Chimia99-53-275

Substrate/catalyst (s/c) ratio given as 800, thus assumed this was generated from a 1:1 ligand:metal  ratio (not explicitly stated in paper). A description of the extension of this reaction as the key process in the production of > 10000 t/y of (S)-metolachlor is given in Chimia99-53-275. Optimised conditions = H2 (80 bar), 50 oC, s/c > 1000000, reaction time = 4 h, 79% ee, 100% conversion. Other exact details of the process are not given, but assuming the catalyst is generated from the same ratio of ligand/metal components in the scheme, and for s/c = 1000000, ACE = 133970. Stated that it proved possible to further decrease the catalyst loading to give a s/c ratio of 2000000.

JOMC01-621-34

PP-Josiphos_JOMC01-621-34

Absolute configuration of product not stated so assigned by comparison to the use of the same (R,Sp)-ligand for the synthesis of (S)-Metolachor (Chimia99-53-275). Substrate/catalyst ratio given as 250 thus assumed this was generated from a 1:1 ratio ligand:metal (not explicitly stated in paper).

CEJ12-18-11578

PP-Josiphos_CEJ12-18-11578

Dalton15-44-19566

PP-Josiphos_Dalton15-44-19566

Copper

Cu – Grignard Conjugate addition

PNAS04-101-5837

PP-Josiphos_PNAS04-101-5834

JACS04-126-12784

PP-Josiphos_JACS04-126-12784

Angew05-44-2752

PP-Josiphos_Angew05-44-2752

No difference between in situ formed and preformed catalyst. Very slow reaction with MeMgBr. Josiphos-2 better for bulky/aryl beta-substituents.

JACS05-127-9966

PP-Josiphos_JACS05-127-9966

Thioesters more reactive towards conjugate addition than corresponding oxoesters (closer to enones). Basis of an iterative methodology demonstrated with the synthesis of (-)-lardolure. Also applied  to the synthesis of mycocerosic acidphthioceranic acid, a putative wasp pheromone, a simplified analogues of caspofunginmycolipenic acid and glycolipid antigens.

JACS06-128-14977

PP-Josiphos_JACS006-128-14977

Conversion of the crude aldol product to the oxygen ester gave greater stability for diastereoisomer purification (column chromatography and in some cases crystallisation). Use of an alkyl β–substituent in the unsaturated thioester substrate (CH2OTBDPS) resulted in poor aldol diastereoselectivity (~1:1).

ASC07-349-1931

PP-Josiphos_ASC07-349-1931

A higher ee value but a lower yield was obtained from the use of a (S,R,R)-phosphoramidite ligand with Me2Zn [95% ee (S), 12% yield] or AlMe3 [96% ee (R), 16% yield].

JOC08-73-6994

PP-Josiphos_JOC08-73-6994

 

Josiphos-1 was also applied to reaction of the corresponding methyl ketone (R = Me). (R,Sp)- Josiphos-1 resulted in the anti isomer in high dr (92 : 8 with EtMgBr and 98:2 with MeMgBr). In contrast (S,Rp)-Josiphos-1 resulted in poor syn selectivity.

OL07-9-5123

PP-Josiphos_OL07-9-5123

Substrates containing an aryl substituent at the beta position are generally less reactive towards conjugate addition with Grignard reagents. This paper goes on to report that higher activities and high enantiomeric excesses were observed with Tol-BINAP as ligand.

Angew10-49-6195

PP-Josiphos_Angew10-49-6195

The SiMe2Ph may be replaced (with retention of configuration) by a hydroxyl group using a Tamao-Fleming oxidation.

ASC14-356-2061

PP-Josiphos_ASC14-356-2061

JACS15-137-8983

PP-Josiphos_JACS15-137-8983

 

Cu – Organoaluminium/Zinc Conjugate addition

CEJ13-19-11352

PP-Josiphos_CEJ13-19-11352

Cu – Enolate Conjugate addition (Michael Reaction)

Angew11-50-12355

PP-Josiphos_Angew11_50_12335

This reaction was exemplified and extended using phosferrox ligand PN-L1a which also resulted in high enantioselectivity.

Cu – Addition of Grignard reagents to ketones

CC12-48-1478

PP-Josiphos_CC12-48-1478

No reaction with MeMgBr and a racemic product obtained with PhMgBr. Absolute configuration not stated.

OBC12-10-2878

PP-Josiphos_OBC12-10-2878

Absolute configurations are implied in the manuscript schemes but it is not stated how determined. However the supporting information states that the absolute configurations were not determined, thus not given here. A marked positive non-linear effect (asymmetric amplification) has been reported for this reaction due to the selective precipitation of the meso (R,SP,S,RP) dimer under the reaction conditions. See: CC13-49-5450.

Angew12-51-3164

PP-Josiphos_Angew12-51-3164

Absolute configuration assigned by  comparison of the sign of the optical rotation of the products with that of (R)-2- phenylbutan-2-ol, a compound not synthesised using this methodology.

Cu – Grignard allylic substitution

CC06-409

PP-Josiphos_CC06-409

Higher ee values obtained with a Taniaphos ligand. Absolute configuration assigned by comparison to results reported in JACS06-128-15572.

JACS06-128-15572.

PP-Josiphos_JACS06-128-15572

Higher ee values obtained with a Taniaphos ligand.

Cu – Alkylation of acylsilanes

Angew15-54-3038

PP-Josiphos_Angew15-54-3038_1

Absolute configuration not stated. Low conversion and racemic product obtained with MeMgBr.

Cu – SN2′ Grignard addition to 1,3-cyclohexadiene monoepoxide Synlett07-435

PP-Josiphos_Synlett07-435

The product was much easier to isolate as its acetate. The use of alkylmagnesium bromides resulted in competitive bromide ion attack on the substrate.

Cu – Hydroboration

Angew13-52-3989

PP-Josiphos_Angew13-52-3989_1

Cu – Beta (1,4) borylation

Angew08-47-145

PP-Josiphos_Angew08-47-145

Similar ee values obtained with Mandyphos-1.

CEJ09-15-1939

PP-Josiphos_CEJ09-15-1939

Mandyphos-1 also applied to this reaction.

ASC09-351-855

PP-Josiphos_ASC09-351-855

JACS10-132-17109

PP-Josiphos_JACS10-132-17108

Inversion of stereochemistry on transmetallation to palladium a unique feature of the reactivity of beta-trifluoroboratoamides due to participation of the  carbonyl oxygen.

ASC11-353-376

PP-Josiphos_ASC11-353-376

The syn N-n-butyl derivative was generated in the same way in 80% ee. The syn N-phenyl derivative was similarly generated in 92% ee, 69% yield using a phosphoramidite ligand.

CC11-47-6701

PP-Josiphos_CC11-47-6701

Similar ee values and the same absolute configuration obtained with (R,Rp)-Taniaphos-1. MeOH added to a solution containing all of the other species – this resulted in an increase in reactivity.

OL12-14-2406

PP-Josiphos_OL12-14-2406_1

Complete catalyst control with imperfect asymmetric induction.

ChemCatChem13-5-2233

PP-Josiphos_ChemCatChem13-5-2233

Absolute configuration not stated for the products resulting from the latter reaction.

ChemCatChem15-7-660

PP-Josiphos_ChemCatChem15-7-660

In situ generation of corresponding alpha,beta-unsaturated carbonyl compound. For enones higher ee values with a Taniaphos ligand.

JOC17-82-1951

PP-Josiphos_JOC17-82-1951

Lower enantioselectivity with strongly electron withdrawing substituents or, in general, ortho substituents.

Cu – Beta (1,4) borylation and enolate trapping

Angew12-51-10827

PP-Josiphos_Angew12-51-10827

Cu – Delta (1,6) borylation

Angew14-53-4186

PP-Josiphos_Angew14-53-4186

With R = Ph a complex mixture resulted. With R = Cy gave beta (1,4)-addition with the resulting alcohol following oxidation obtained in 87% ee.

Cu – Beta (1,4) hydride addition (reduction)

Angew03-42-4789

PP-Josiphos_Angew03-42-4789

The representative procedure in the paper and the SI state CuH.PPh3 as the copper reagent used. In contrast the tables in the paper give this as CuCl. A Walphos ligand has also been applied successfully to a small number of examples.

Angew06-45-2785

PP-Josiphos_Angew06-45-2785

Synthesis07-2233 (essentially identical to the above paper)

PP-Josiphos_Synthesis07-2233

OL07-9-2749

PP-Josiphos_OL07-9-2749

 

The absolute configuration of the product of the representative reaction is given as S which fits with other Cu-catalysed reductions with (R,Sp)-Josiphos-1. The structure of this product is incorrectly drawn as R in the supporting information.

JACS09-131-10386

PP-Josiphos_JACS09-131-10386

JOC09-74-4232

PP-Josiphos_JOC09-74-4232

Under the same conditions the (E)-diastereoisomer of the substrate gave the S product in 86% ee, 91% yield.

CEJ09-15-11134

PP-Josiphos_CEJ09-15-11134

Synlett10-2041

PP-Josiphos_Synlett10-2041

Micellar catalysis in water using surfactant TPGS-750-M with PMHS as hydride source.

Tet12-68-3428

PP-Josiphos_Tet12-68-3428

 

Tet12-68-3444

PP-Josiphos_Tet12-68-3444

Cu – 1,3-Enyne/aldehyde coupling

JACS14-136-11304

PP-Josiphos_JACS14-136-11304

Cobalt

Silylacetylene addition to 1,1-disubstituted allenes

JOC13-78-8986 

PP-Josiphos_JOC13-78-8986

Nickel

Hydrogenation ChemCatChem09-1-237

PP-Josiphos_ChemCatChem09-1-237

A dynamic kinetic resolution.

Allylic amination OL04-6-2661

PP-Josiphos_OL04-6-2661

Ligand screening gave the highest ee with (R,Sp)-Josiphos-3 but a significantly higher yield (75% ee, 83% yield of (S)-product) with (R)-MeO-BIPHEP. No base was required for this reaction.

Organocatalysis

JOC10-75-7901

PP-Josiphos_JOC10-75-7901