This application claims pπoπty to the follow ing L ^' S prov isional applications

60/019,93S filed on June 14. 1996, 60/033,493 filed on December 20. 1996, and 60/ filed on May 9, 1997

Technical Field of the Invention

The present inv ention relates to πgid chiral ligands useful in making catalysts for asymmetπc synthesis More particularly, the present inv ention relates to new monodentate and bidentate cyclic chiral phosphine ligands w hich are formed into catalysts to prov ide high selectivity of the enantiomeπc structure of the end-product

Background of the Invention

The biological activities of many pharmaceuticals, fragrances, food additives and agrochemicals are often associated with their absolute molecular configuration While one enantiomer gives a desired biological function through interactions with natural binding sites, another enantiomer usually does not have the same function and sometimes has deleteπous side effects A growing demand in pharmaceutical industπes is to market a chiral drug in enantiomeπcally pure form To meet this challenge, chemists have explored many approaches for acquiπng enantiomeπcally pure compounds ranging from optical resolution and structural modification of naturally occurring chiral substances to asymmetπc catalysis using synthetic chiral catalysts and enzymes Among these methods, asymmetπc catalysis is often the most efficient because a small amount of a chiral catalyst can be used to produce a large quantity of a chiral target molecule Dunng the last two decades, great effort has been devoted to discoveπng new asymmetπc catalysts and more than a half-dozen commercial industπal processes have used asymmetπc catalysis as the key step in the production of enantiomeπcally pure compounds

Asymrnetnc phosphine ligands have played a significant role in the development of novel transition metal catalyzed asymrnetnc reactions O er 1000 chiral diphosphines-

have been made since the application of the DIPAMP for the industπal production of L-Dopa, yet only a few of these ligands afford the efficiency and selectiv ity required for commercial applications Among these ligands, BFNAP is one of the most frequently used bidentate chiral phosphmes The axially dissymmetπc. fully aromatic BΓNAP ligand has been demonstrated to be highly effective for many asymrnetnc reactions Duphos and related ligands have also shown high enantioseiectiv mes in numerous reactions However, there are a v aπety of reactions in hich only modest enantioselectiv ity has been achiev ed w ith these ligands Highly selectiv e chiral ligands are needed to facilitate asym etπc reactions Figure 1 lists known chiral bidentate phosphmes (DIP AMP, ^ BPPM." ¹

DEGPHOS, ⁵ DIOP, ⁶ Chiraphos, ⁷ Skewphos, ⁸ BLNAP, ⁹ Duphos, ¹⁰ and BPE ¹⁰ ) While high selectivities were observ ed in many reactions using some of these chiral diphosphine ligands, there are many reactions w ere these ligands are not very efficient in terms of activ ity and selectivity There are many disadvantages associated with these ligands, which hinder their applications For DIPAMP, the phosphine chiral center is difficult to make This ligand is only useful for asymrnetnc hydrogenation reaction For BPPM, DIOP and Skewphos, the methylene group in the ligands causes conformational flexibility and enantioselectivities are moderate for many catalytic asymrnetnc reaction DEGPHOS and CHIRAPHOS coordinate transition metal in five-membered πng The chiral environment created by the phenyl groups is not close to the substrates and enantioseiectiv mes are moderate BI AP, DuPhos and BPE ligands are good for many asym etπc reactions However, the rotation of aryl-aryl bond makes BINAP very flexible The flexibility is an inherent limitation in the use of phosphine ligands Fuπhermore, because the BINAP contains three aryl groups, it is less electron donating than phosphmes that have less aryl groups This is an important factor w hich influences reaction rates For hydrogenation reactions, electron donating phosphmes are more active For the more electron donating DUPHOS and PBE ligands, the fiv e membered nng adjacent to the phosphmes is flexible

U S Patents 5,329,015, 5,386,061 , 5,532,395 descπbe phosphmes prepared through chiral 1 , 4-dιols These patents also descπbe divalent aryl and ferrocene bπdging groups U S Patent 5,258,553 descπbes chiral tndentate ligand phosphine ligands The

above ligands are made into Group VIII transitional catalyst and are used to conduct enantioselective catalytic reactions such as asymmetπc hydrogenation of olefins, ketones and lmines These references illustrate the preparation of catalyst from phosphine ligands and the conducting of vaπous asymmetπc synthesis These patent disclosures are incorporated herein by reference

The present invention discloses several new bidentate and monodentate phosphine ligands for asymmetπc catalysis The common feature of these ligands are that they contain πgid πng structures useful for restπcting conformational flexibility of the ligands, thus enhancing chiral recognition The present invention prov ides families of chiral diphosphines by v aπation of the steπc and electronic environments (I e , change of P-M-P bite angles and substituents on phosphine) In such a manner, the present invention prov ides an efficient and economical method w ith which to synthesize chiral drugs and agrochemicals

Brief Description Of The Figures Figure 1 list known chiral bidentate phosphmes W ile high selectivities were obtained in many reactions using some of these chiral diphosphine ligands, there are many reactions here these ligands are not v ery efficienct in terms of activity and selectivity There are many disadvantages associated with these ligands, which hinder their applications For DIPAMP, the phosphine chiral center is difficult to make This ligand is only useful for limited application in asymmetπc hydrogenation For BPPM,

DIOP, and Skewphos, the methylene group in the ligands causes conformational flexibility and enantioseiectivmes are moderate for many catalytic asymrnetnc reactions

DEGPHOS and CHIRAPHOS coordinate transition metals m five-membered πng The

Chiral environment created by the phenyl groups is not close to the substrates and enantionselectivities are moderate for many reactions BINAP, DuPhos and BPE ligands are good for many asym etπc reactions However, the rotation if aryl-aryl bond makes

BINAP very flexible The flexibility is an inherent limitation in the use of phosphine ligand Furthermore, because the phosphine of BINAP contains adjacent three aryl groups , it is less electron donating than phosphine that hav e less aryl groups This is an important factor which influences reaction rates For hydrogenation reactions, electron

donating phosphmes are more active. For the more electron donating DUPHOS and BPE ligands, the five-membered nng adjacent to the phsophines is flexible.

Figure 2 illustrates ligands 1 -13 (Type I). These ligands have at less four chiral centers in their backbones and they can form seven-membered chelating πng w ith many transition metals The two cyclic πngs in the backbone limit the conformational flexibility. The two carbon stereogenic centers adjacent to PR, may be inverted as illustrated m Figure 2.

Figure 3 deptcts ligands 14-23. Ligands 14-16 (Type II) have a nitrogen- phosphme bond in the ligands. Ligands 17-19 (Type III) have many phosphine-oxygen bonds Ligands 20-23 (Type IV) have spiro-nng structure in their backbones These ligands can be regarded as deπvatives of ligands 1 - 13 w ith structure vaπation of their backbones.

Figure 4 depicts ligands 24-34 (Type V), chiral phosphmes w ith phospha-tπcyclic structures. Figure 5 and 6 illustrate type VI chiral phosphmes with fused phospha-bicyclic structures.

Figure 7 shows type VII chiral phosphine ligands having one or two πngs in their backbones.

Figure 8 outlines the synthesis of the type I ligands, 1 - 13 Asymmetπc hydroboration of dienes or hydroboration of chiral dienes can lead to chiral 1 ,4-dιols Chiral resolution of diols can also provide an effective routes to chiral diols Dienes and chiral dienes may be generated using vaπety of methods including but not limited to Pinacol coupling and elimination, aldol condensation followed by reduction and elimination, Methathesis, and coupling of vinyl halide or vinyl lithium. Mesylation of diols and nucleophilic attack of mesylates with a vaπety of phosphides can produce the desired products. With chiral dienes, the free-radical addition of HPR2 may lead to the products. For the inversion of the chiral diol, Mitsunobo reaction may be applied

Figure 9 illustrates the synthesis of ligands 14-23 For the chiral ligands containing P-O or P-N bonds, the corresponding chiral diols or chiral diamines are presented. For the spiro phosphmes, one pathway is to construct spiro-structure in the

last step This is because direct nucieophilic attack by LiPPln to the corresponding spiro dimesylate is difficult due to the steπc hinderance of adjacent carbon group

Figure 10 descπbes the synthesis of phospha-tπcychc compounds from the corresponding diols Figure 1 1 and 12 descπbes the synthesis of chiral fused phospha-bicyclic compounds. A typical procedure uses RPL12 as nucieophiles However, phospha- bicyclic anion can be made and nucieophilic attack with bπdge groups (XKX or RX here R is alkyl or aryl and X is a hahde, tosylate or mesylate) by this anion can generate the desired ligands Figure 13 outlines the synthetic procedures for ligands 45 to 50

Figure 14 illustrates applications of asymmetπc catalytic reactions

Summary Of The Invention

It is an objective of the present invention to provide a chiral diphosphine ligand that pro ides high enantioselectivity and activity The present invention therefore provides a chiral phosphine ligand having a conformationally πgid cyclic structure, in which the phosphorus may be bonded to or be part of the cyclic structure. As such, the ligand πgidity provides enhanced chiral discπmination in metal catalyzed asymmetπc organic reactions. In one embodiment, a "type I" or ''type II" chiral bidentate phosphine ligand having a 2,2'-bιs(dιorganophosphιno)-l ,r-bιs(cyclιc) structure wherein each cycle of the bιs(cyclιc) structure compπses 3 to 8 carbon atoms wherein the 1, 1 ', 2 and 2' carbon atoms in the bιs(cychc) structure are saturated carbon atoms and wherein the carbon atoms in the bιs(cyclic) structure other than the I , 1 ', 2 and 2' carbon atoms are optionally replaced with a heteroatom including but not limited to nitrogen, oxygen or sulfur; and wherein type II ligands have nitrogen in the 2.2' position, is provided

In another embodiment, a "type III" chiral bidentate phosphine ligand having a l ,r-bιs(cyclic)-2,2'(organophosphιnιte) structure is provided.

In yet another embodiment, a "type IV" chiral phosphine ligand having a heteroatom-contaming spπo bis-organophosphine or organophosphinite is provided. In one embodiment, a "type V" chiral bidentate phosphine ligand having a

(bts)phospha-tncyclιc structure with a bπdge group is pro ided.

In another embodiment, a "type VI ^" chiral phosphine ligand having a (bιs)fused phospha-bicyclic structure comprising a bridge structure is provided.

In yet another embodiment, a "type Vila" chiral phosphine ligand having a cis(bis) phosphine fused bicyclic structure is prov ided. In one embodiment, a "type Vllb" chiral phosphine ligand having a cis or trans biphosphine cyclic structure having two R' substituents where R' is alkyl, fluoroalkyi or perfluoroalkyl (each having up to 8 carbon atoms), aryl, substituted aryl, arylalkyl, πng- substituted arylalkyl, and -CR'2(CR'2)qZ(CR ^, ) _p R ^* where q and p are the same or different integers ranging from 1 to 8 and Z is defined as O, S, NR, PR, AsR, SbR. divalent aryl, divalent fused aryl, divalent 5-membered πng heterocyclic group, or a div alent fused heterocyclic group where R is alkyl of 1 -8 carbon atoms, aryl, or substituted aryl is provided. In another embodiment, a "type VTIc" chiral phosphine ligand having a trans(bis) phosphine bicyclic structure.

In yet another embodiment, a "type V ^" chiral monodentate phosphine ligand compnsing a phospha-tπcyclic structure is provided.

.And, in yet another embodiment, a "type VI" chiral monodentate phosphine ligand comprising a phospha-bicyclic structure is provided.

.And, in yet another embodiment, a cyclic phosphine ligand having a structure of :

A. Bidentate cyclic chiral phosphmes:

or

B. monodentate cyclic chiral phosphines

where each R is independently alkyl of 1-8 carbon atoms, substituted alkyl, aryl, or substituted aryl; each R' is independently alkyl, fluoroalkyl and perfluoroalkvl, each having up to 8 carbon atoms; aryl; substituted aryl; arylalkyl; ring-substituted arylalkyl; and -CR'2(CR'2) _q Z(CR'2)pR' wherein q and p are the same or different integers ranging

from 1 to 8, R' is as defined above, and Z is selected from the group consisting of O. S.

NR, PR, AsR, SbR, divalent aryl, divalent fused aryl, divalent 5-membered πng heterocyclic group, and a div alent fused heterocyclic group where R is as defined above, the cyclic structure D represents a πng hav ing 3 to 8 carbon atoms w hich may be substituted within the πng with one or more oxygen, sulfur, N-R\ C=0, or CR\, D represents 0 to 8 carbon atoms, and where the nng may further be substituted with R' as defined abov e, the Bπdge is -(CH2) _r - where r is an integer ranging from 1 to 8, -

(CH2) _s Z(CH2) _m - wherein s and m are each the same or different integers ranging from 1 to 8, 1 ,2-dιvalent phenyl. 2.2'dιvalent- l , rbιpheny l, 2.2'dιvalent 1 ,2'bιnapthyl, and ferrocene, each of which may be substituted w ith R' as defined above, and where the substitution on 1 ,2-dιvalent phenyl, the ferrocene or biaryl bπdge is independently hvdrogen, halogen, alkyl, alkoxyl, aryl, aryloxy nitro, amino, v inyl, substituted vinyl. alkynyl. or sulfonic acid, X is O, S or NR where R is as defined above, and n is 1 or 2

It is yet another objective of the present inv ention to provide a catalyst that provides high enantioselectiv ity and activity, in one embodiment of the present invention, a chiral phosphine ligand as descπbed abov e complexed with a transition metal, preferably rhodium, indium, ruthenium, palladium or plati um is provided

In certain compounds of the present inv ention, the phosphine ligand is attached to an organic substrate or backbone by a chemical bπdging group or organic substituent For these compounds, it is preferred that the chemical bπdgmg group or organic substituent has a linker to a polymer The polymer-supported catalyst is a heterogenous or homogenous catalyst, dependent upon the solubility of the poiymer in the reaction medium

It is another objective of the present in ention to provide a method for transition metal complex catalyzed asym etπc hydrogenation of ketones, immes, or olefin, tn one embodiment, a method is provided in which such a reaction is catalyzed by a chiral phosphine ligand as described above complexed w ith a transition metal, preferably rhodium, indium, ruthenium, palladium or platimum is provided

It is yet another objective of the present invention to prov ide an improv ed method for a transition metal catalyzed asymrnetnc reaction such as hydrogenation, hydπde transfer reaction, hydrosilylation, hydroboration, hydrov inylation, hydro formylation.

hydrocarboxylation, allylic alkylation, cyciopropanation, Diels-Alder reaction, Aldol reaction, Heck reaction, Michael addition, and stereo-selective polymenzation in one embodiment, the improvement comprising catalysing the reaction with a catalyst that is a chiral phosphine ligand as described above complexed with a transition metal, preferably rhodium, indium, ruthenium, palladium or platimum. In yet another embodiment, the catalyst is selected from the group consisting of compound 1 as illustrated in Figure 1. compound 36 as illustrated in Figure 5, compound 40 as illustrated in Figure 6, and compound 26 as illustrated in Figure 4. In another embodiment, the catalyst is a complex of a chiral phosphine complexed with a compound that is [Rh(COD)Cl]2, [Rh(COD)2]X (X = BF , ClO , SbF ₆ , CF3SO3), [Ir(COD)Cl] ₂ , [Ir(COD) ₂ ]X (X = BF ₄ , CIO4. SbF ₆ ,

CF3SO3,), Ru(COD)CIj, [Pd(CHjCN) [BF ) ₂ , Pdaflba),, and [Pd(C ₃ H ₅ )Cl] ₂ . And, in yet another embodiment, the catalyst is Ru(RCOO)2(Y), RuX2(Y), Ru(methylally ),(Y),

Ru(aryl gτoup)X2(Y), where where X is Cl, Br or I and Y is a chiral diphosphine of the present invention. It is yet another objective of the present invention to provide an improved method for asymmetric hydration of a ketone, imine or olefin catalyzed by a complex compπsing

Ru, Rh and Ir and a chiral ligand; in one embodiment, the improvement includes conducting the catalysis with a palladium complex having a chiral phosphine ligand as descπbed above. In yet another embodiment, the catalyst is selected from the group consisting of compound 1 as illustrated in Figure 1, compound 36 as illustrated in Figure

5, and compound 26 as illustrated in Figure 4.

It is another method of the present invention to provide an improved method for asym etπc allyl c alkylation catalyzed by a complex comprising palladium and a chiral ligand; in one embodiment, the improvement includes catalysis with a palladium complex having a chiral ligand as desenbed above. In yet another embodiment, the catalyst includes compound 40 as illustrated in Figure 6.

It is yet another objective of the present invention to provide an intermediate for synthesis of a chiral phosphine ligand. In one embodiment, the intermediate shown as compound 3 in Scheme 2 is provided.

XR, PR. AsR, SbR, divalent aryl, div alent fused aryl, divalent 5-membered πng heterocyclic group, and a divalent fused heterocyclic group where R is as defined above, the cyclic structure D represents a πng having 3 to S carbon atoms w hich may be substituted w ithin the πng with one or more oxygen, sulfur, N-R\ C=O, or CR\, represents 0 to S carbon atoms, and where the nng may further be substituted with R' as defined above, the Bπdge is -(CH2) _r - w here r is an integer ranging from 1 to 8, - (CH2) _s (CH )m- wherein s and m are each the same or different integers ranging from 1 to 8, 1 ,2-dιvalent phenyl, 2,2'dιvalent- l,rbιphenyl, 2,2'dιvalent 1,2'bmapthyl, and ferrocene, each of which may be substituted w ith R' as defined above, and where the substitution on 1.2-dιvalent phenyl, the ferrocene or biaryl bπdge is mdependentlv hydrogen, halogen, alkyl, alkoxyl, aryl, aryloxy, nitro. amino, vinyl, substituted v inyl alkynyi, or sulfonic acid, X is O, S or NR where R is as defined above, and n is 1 or 2

It is yet another objective of the present inv ention to provide a catalyst that provides high enantioselectivity and activity , in one embodiment of the present invention, a chiral phosphine ligand as descπbed above complexed with a transition metal, preferably rhodium, indium, ruthenium, palladium or platimum is provided

In certain compounds of the present in ention, the phosphine ligand is attached to an organic substrate or backbone by a chemical bπdging group or organic substituent For these compounds, it is preferred that the chemical bπdging group or organic substituent has a linker to a polymer The polymer-supported catalyst is a heterogenous or homogenous catalyst, dependent upon the solubility of the polymer in the reaction medium

It is another objective of the present invention to provide a method for transition metal complex catalyzed asymmetπc hydrogenation of ketones, immes, or olefin, in one embodiment, a method is provided in w hich such a reaction is catalyzed by a chiral phosphine ligand as descπbed above complexed with a transition metal, preferably rhodium, indium, ruthenium, palladium or platimum is provided

It is yet another objective of the present invention to provide an improved method for a transition metal catalyzed asymrnetnc reaction such as hydrogenation, hydπde transfer reaction, hydrosilylation, hydroboration, hydrovinylation, hydro formylation, hydrocarbox lation, allylic alkylation, cyclopropanation. Diels-Alder reaction, Aldol

reaction, Heck reaction, Michael addition, and stereo-selective polymerization in one embodiment, the improvement comprising catalysing the reaction with a catalyst that is a chiral phosphine ligand as described above complexed with a transition metal, preferably rhodium, iridium, ruthenium, palladium or platinium. In yet another embodiment, the catalyst is selected from the group consisting of compound 1 as illustrated in Figure 1 , compound 36 as illustrated in Figure 5, compound 40 as illustrated in Figure 6, and compound 26 as illustrated in Figure 4. In another embodiment, the catalyst is a complex of a chiral phosphine complexed with a compound that is [Rh(COD)Cl]2, [Rh(COD)2JX (X = BF ₄ . C10 ₄ , SbF ₆ , CF3SO3), [Ir(COD)Cl] ₂ , [lτiCOO) ₂ ]X (X = BF ₄ . CIO ₄ , SbF ₆ , CF3SO3,), Ru(COD)CI ₂ , [Pd(CH,CN) ₄ [BF ₄ } ₁ , Pd,(dba),and [Pd(C ₃ H ₅ )CI] . And, in yet another embodiment, the catalyst is Ru(RCOO)2(D. RuX ₂ (Y), Ru(methylallyl) _: (Y), Ru(aryl group)X2(Y), where where X is Cl, Br or I and Y is a chiral diphosphine of the present invention.

It is yet another objective of the present invention to provide an improved method for asymmetric hydration of a ketone, imine or olefin catalyzed by a complex comprising Ru, Rh and Ir and a chiral ligand; in one embodiment, the improvement includes conducting the catalysis with a palladium complex having a chiral phosphine ligand as described above. In yet another embodiment, the catalyst is selected from the group consisting of compound 1 as illustrated in Figure 1, compound 36 as illustrated in Figure 5, and compound 26 as illustrated in Figure 4.

It is another method of the present invention to provide an improved method for asymmetric allyllic alkylation catalyzed by a complex comprising palladium and a chiral ligand; in one embodiment, the improvement includes catalysis with a palladium complex having a chiral ligand as described above. In yet another embodiment, the catalyst includes compound 40 as illustrated in Figure 6.

It is yet another objective of the present invention to provide an intermediate for synthesis of a chiral phosphine ligand. In one embodiment, the intermediate shown as compound 3 in Scheme 2 is provided.

Detailed Description

In the descπption of the cyclic chiral phosphine ligands above the term aryl includes phenyl, furan, thiophene. pyridine, pyτole, napthyl and similar aromatic nngs

Substituted aryl and substituted vinyl refer to an aryl or vinyl, respectively, substituted w ith one or more alkyl groups having l -S carbon atoms, alkoxy having 1 -8 carbon atoms. alkylcarbonyl having 1 -8 carbon atoms, carboxy, alkoxycarbonyl having 2-8 carbon atoms, halo (Cl, Br, F or I) ammo, alkylamino or dialkylamino

An suitable aryl, divalent aryl or divalent fused aryl for use in the present invention includes but is not limited to those deπved from the parent compound benzene. anthracene or fluorene. A suitable 5-membered ring heterocyclic group for use herein includes but is not limited to one deπv ed from the parent heterocyclic compound furan. thiophene, pyrrole, tetrahydrofuran, tetrahydrothiopene. pyrrolidine, arsole or phosphole.

A suitable fused heterocyclic group for use herein includes but is not limited to one deπved from the parent compound bipyπdine, carbazoie. benzofuran, indole, benz- pyrazole, benzopyran, benzopyronone or benzodiazme. A suitable ary loxy group for use in the present invention includes but is not limited to an aryl having an oxygen atom as a substituent.

Alkyls having 1-8 carbon atoms includes straight or branched chain alkyls and cycloalkyls having 3 to 8 carbon atoms. Representative examples are methyl, ethyl. propyl, isopropyl, butyl, tertiary butyl, pentyl, cyclopentyl, hexyl cyclohexyl and the like. The alkyl group may be substituted with phenyl, substituted phenyl or alkoxy, carboxy, alkyoxycarbonyl, halo, ammo, or alkyl amino or dialkylamino as defined above Certain compounds of the present invention provide a phosphine ligand attached to an organic substrate or backbone. In such cases, the chemical bπdging group or the allyl or akyl groups adjacent to phosphine may include a linker to a polymer; the polvmer supported-catalyst is a heterogenous or homogenous catalyst dependent upon the solubility of the polymer in the reaction medium.

Those skilled in the chemical art will recognize a w ide vanety of equiv alent substituents

The cyclic chiral phosphine ligands of the present mventton are reacted w ith transition metals to form catalyst. Preferably Group VIII transition metals are used and most preferably the catalyst is formed with rhodium, indium, ruthenium, or palladium

The invention encompasses a vaπety of asymmetπc reactions utilizing catalyst of the invention, such as hydrogenation, hydπde transfer, hydrosilylation, Gπgnard Cross- coupling, hydrocyanation, isomeπsation, cycloadditions, Sigmatropic rearrangement, hydroboration, hydro formylation, hydrocarboxylation. allylic alkylation, hydrov inylaiion. cyclopropaπation, aldol reaction. Heck reaction, Michael addition, and stereo-selective poiymenzation can be earned out with these ligand systems The catalyst of this invention provides efficient and practical methods for producing chiral drugs for antihypertensive, antihistamine, cardiovascular and central nervous system therapies The transition metal complexes of cyclic chiral phosphine ligands of the present invention are also important in the production of chiral agrochemicals.

The invention is illustrated by the synthesis and application of a chiral 1 ,4- bisphosphme, (2R, 2'R)-bjs(dιphenylrjhosphιno)-(I R, I'Rj-dicyclopentane (1) (abbreviated (R, R)-BICP) (Scheme 2) in the rhodium catalyzed asymrnetnc hydrogenation of α-(acylamιno)acryhc acids An important feature of this ligand is that it contains two cyclopentane πngs in its backbone which are present to restπct us conformational flexibility leading to high enantioselectiv ity in asymrnetnc reactions

uadrants

BΙCP (t ) Side View T.p V.e v

Scheme 1

The bisphosph e ligand (1, R, R-BICP) was synthesized from readily available l ,l'-dιcyclopentene (2)" as shown in Scheme 1 Asymrnetnc hydroboration of 2 using

(-)-monoιsopιnocamphenylborane [(-r) lpcBH2] followed by oxidation w ith H2θ2' ^: gave the desired chiral diol (3) ( 100% ee after recrystallization from ether hexanes). w hich was then converted to the dimesylate in high yield. Subsequent reaction of the dimesvlate ith lithium diphenylphospine afforded the bisphosphine 1

IMSCI El N C H-CI I ) LiPPh- THF : r V--

HO

¹ 3 R. R- BICP 1

Scheme 2

Hydrogenation of α-acetoamidocinnamic acid was earned out at rt and 1 atm of hydrogen in the presence of the catalyst formed in situ from [Rh(COD)2]BF4 and bisphosphine 1 ( 1 1 .1 ) Table 1 shows the results of hydrogenation of - acetoamtdocinnamic acid under a vaπety of conditions. The addition of a catalytic amount of triethylamine (Rh:I :Et3N= l : l . l :50) gave a better optical yield than w ithout tπethylamine (Entry 1 vs 2). This effect may be due to a conformational change in the chiral Rh complex, since the carboxylate anion generated from the substrate and tπethyiamine has a greater affinity for the metal than the coσesponding acιd.^ ^a The enantioselectivity in the hydrogenation was found to be highly dependent on the nature of the Rh complex. When a neutral Rh complex was used as the catalyst precursor, the optical yield decreased dramatically (entry 3). The highest selectivity (96.8%, S) for the hydrogenation of α-acetoamidocinnamic acid was obtained in THF at 1 atm of H2 in the presence of triethylamine (entry 4), while changing substrate, catalyst ratio had a small effect on the enantioselectivities (entry 4 vs 5).

TABLE 1

Optimization of the asymmetric hydrogenation of α-acetamidocinnamic acid ¹

EtOH 89 2

EtOH 50 93 3

EtOH 50 83 6

CICH -CH.CI 50 93 4

THF 50 96 8

THF 95

a The reaction was carried out at rt under I atm of H for 24 h [substrate (0 5 mmol. 0, 1 5

M) lιgand(l ) = 1 .0.01.0.0 ! I ] The reaction went m quantitative > ιeld b Determined by GC using aChirasil-V AL III FSOT column on the corresponding I ester The S absolute configuration was determined bv comparing the optical rotation with the reported v alue. c 0 5 mol° o [Rh(COD)Cl] _: was used as the catalyst precursor d 0 l mol °i [Rh(COD) _: ]BF ₄ /0 1 1 mol ⁰ o ligand ( l)/5 moI Et ₃ N were used.

The metholology is useful in the asymrnetnc synthesis of chiral amino acids. Tables 2 and 3 show the enantioselectivity of some amino acids obtained by hydrogenation of α-(acylamino)acr lic acids under an optimum condition. Enanttoselectivities in this hydrogenation were not sensitive to the substitution pattern on the β-position of the prochiral olefin substrates, where α-benzamidocinnamic acid gave better optical yields than the corresponding acetoamido deπvative.

TABLE 2 Asymmetric Hydrogenalions of Dehydroamiπo Acid Derivatives

[R (COD),)BF ₄ (1 ~ol%)

XOOH BICP π 1 mol%), Et,Nι50mol' .COOH

+ H ₂ (1 a:m) (S)

NHCOR' THF rt.24 h NHCOR'

Entrv Substrate % ee ²

COOH

100 97.5 -HCOCH ₃

COOH

ι-Pr' VHCOCH ;00 92.6

COOH

J

Ph \HCOCH, 100 96.8

COOH

Ph ^COPh 00 99.0

a. % ee determined by GC using Chirasil-VAL III FSOT Column of the corresponding methyl ester.

TABLE 3 Asymmetric Hvdrogenations of Dehvdroamino Acid Deri ativ es

[Rh(CODH]BF ₄ π -ol%) OOH _B)C p _{( 1} , _mo ,o _{/o) E} , _{N 0 mol} % ₎ COOH

H ₂ ( 1 atm) (S)

NHCOR' THF rt 24 h NHCOR'

Entrv Substrate Con. % O r o ee

a % ee determined by GC using Chirasil-VAL III FSOT Column of the corresponding methyl ester or by HPLC (OJ collumn)

he corresponding methyl ester, the results are summanzed in Table 4

TABLE 4 \sy mmetric Hydrogenations of Methv I Ester of Dehvdroamino Acid Derivativ es

[R (C0Dϊ _: ]BF ₄ (1 τιol%) ,COOCH ₃ BIC i i 1 mol%) COOCH ₃

+ H ₂ ( 1 atm) (S)

NHCOCH ₃ THF n 24 NHCOCH,

Entry Substrate Con. % Vo ( )

H 100 76.2

// V 100 78.4

a. % ee determined by GC using Chirasil-VAL III FSOT Column b 50mol% Et ₃ N was added

Table 5 illustrates comparative asymrnetnc hydrogenations of dehydroammo acid den atives

TABLE 5 As mmetric Hydrogenations of Dehvdroamino Acid Derivatives

COOH Rh(COD)(P-P)X COOH

/ R NHCOR H _: X = BF \ CIO/ R NHCOR

P-P = chiral diphenv iphosphine (° o ee)

Substrate DiPAMP BrNAP CHIRAPHOS BPPM DIOP BICP

COOH

= 94 67 91 98 98

95 84 89 91 97

96 100 99 83 64 99

94 79' 83 86 84 98 ' NΗCOPh

For the asymmetric hydrogenation of imines. rhodium indium-complexes of BICP are effective Table 6 provides some results on this asymmetπc reaction. For an imme substrate, up to 94 % ee has achiev ed and this is among the highest enantioselectivity obtained with group VIII transition metal catalysts coordinated by a chiral phosphine ligand.

TABLE 6 Ir and Rh-Catalyzed Asymmetric Hydrogenation of Imines

I

Phthalimide (4 mol%) H H ₂ (1000 psi), toluene, rt 100 % con, 93.9 % ee

% ee

Rh(COD) ₂ BF ₄ , BICP, i-PrOH,

. NHCOPh .NHCOPh

N ^' H ₂ (200 psi) N

Ph Ph 100 % Con. 60.2% ee

The πgid fused bicyclic [2.2.1] structure represents a new motif in chiral ligand design. Changes in the size of the R group on the πng system can modulate the asymmetric induction and high enantioselectivities can be achieved. Scheme 3 shows the synthesis of new chiral bicyclic phosphmes (abbreviated as PennPhos because it represents a different structure from DuPhos [DuPont Phosphine] and w as made at Perm State).

Scheme 3

Synthesis of PennPhos

lization

a : Me-PennPhos R = CH ₃ 27.5°, o 36b : i-Pr- PennPhos R = i-Pr 42 % Rhodium complexes with PennPhos ligands can be used as cataivts for asymmetric hydrogenation. Table 7 lists the asymmetπc hydrogenation results for dehvdroamino acid deπvatives.

TABLE 7 Asymmetric Hydrogenations of Dehv droamino Acid Derivatives

Me-Peπn Phos

Entrv Substrate Con. °O % ee ³

00 84.3

! 00 52.8

100 82.7

a. % ee determined by GC using Chirasil-VAL III FSOT Column of the corresponding methyi ester. The rhodium complexes with Me-Pennphos are very effective for hydrogenation ple ketones. Up to 97 % ee has been obtained with acetophenone, which is the

11

highest enantioselectivity reported in the direct asymrnetnc hydrogenation oC simpie ketones w ith group VIII transition metal complexes Table 8 summaπzes some results for this study

TABLE 8 Λ.sy mmetric Hv drogenations of Simple Ketones

[Rh(COD)Ci] ₂ 30 atm 97 96 5

[Rh(COD)Ci] ₂ 30 atm ₇₀ 91

[Rh(COD) ₂ ] BF ₄ 70 atm 73 79 6

Synthesis of another chiral cyclic phosphmes is illustrated in Scheme 4 The phospha-tπcychc structure is unique and the phosphmes are made from chiral 1 ,4-dιols with two πngs. Tncvclic structure dictates the chiral en ironment around phosphmes and πng size can be changed by vaπng the chiral diols Both monophosphines and bisphosphines can be made from the straightforward synthetic route They can be used as ligands for many asymrnetnc reactions

Scheme 4

C5 -Tricyclophos 67%

100 ° o ee

Rhodium complexes with these chiral tncvclic phosphmes can be used as cataivts for asymrnetnc hydrogenation. Table 9 lists the asymmetπc hydrogenation results for dehvdroamino acid derivatives.

TABLE 9

Asymmetric Hydrogenations of Dehvdroamino Acid Derivatives

Entry Substrate Con. ° ό % ee ^a

COOMe

Ph NHCOCH ₃ 100 77.6

a. % ee determined by GC using Chirasil-VAL III FSOT Column of the corresponding methyl ester.

The rigid fused bicyclic [2.2.1] structure represents a new motif in chiral ligand design. Analogous to Burk's systems, changes in the size of the R group on the πng system can modulate the asymmetric induction and high enantioselectivities can be achieved. The present invention provides the syntheses of chiral monophosphines with this fused bicyclic ring structure (Scheme 5) and their application in Pd-catalyzed asymmetric allylic alkylations.

SCHEME 5

l ) Lι _; PPh ιn THF rt

2)BH, THF " ^■'

(40)

The ligand synthesis depends on the availability of enantiomeπcally pure cyclic 1 ,4-dιols Haiterman ^u and Vollhardt ¹⁴ have previously prepared chiral cyclopentadiene denv atives from the chiral diols ¹ " ¹⁴ Halterman ^{ι :?} has svnthesized chiral diols 1 and 2 from the inexpensive starting mateπals and p-dπsopropylbenzene, respecti ely The synthesis employed Birch reduction, followed by asymrnetnc hydroboration and recrystalhzation to 100 % ee Con ersion of the optically pure diols to the corresponding mesy lates proceeds cleanly Nucieophilic substitution by L PPh on the chiral dimesylates 3 and 4 generated the corresponding bicyclic phosphmes, which were trapped by BH3*THF to form the air-stable boron-protected monophosphines 5 and 6 respectively Deprotection with a strong acid produces the desired products [7, ( \R, 25, 4Λ, 55)-0)-2, 5-dιmethyl-7-phenyl-7-phosphabιcyclo(2 2 l ]heptane, 8. ( IR, 2R. AR. 5R)- (" ^r )-2. 5-dnsopropyl-7-phenyl-7-phosphabιcyclo-[2 2 l ]heptane] in high yields

Pd-catalyzed allylic alkylation was utilized to test the effecti eness of these new monophosphines as chiral ligands Although many palladium complexes of muitidentate phosphine and nitrogen ligands are excellent catalysts for this reaction, ¹ - palladium complexes of simple chiral monophosphines are normally not effectiv e > - Howe er, Pd- catalyzed allylic alkylation w ith the new monophosphine 7 gave excellent enantioselectivities and conversions (Table 10), comparable to the best results (99 ° ₀ ee) reported to date ¹⁵

TABLE 10 Palladium-Catalyzed Asymmetric Allylic Alkylation with Chiral Monophosphines'

a The reaction was carried out under N using acetate. Nu (nucleophtle) (300 mol° o). BSA ( bιs(tπmeth> lsιlyl)acetamιde) ( 300 mol%). KOAc (2 mol%). toluene. [Pd] 1 moi % and L' b % ee w as measured bv HPLC using a Chiralcel OD column, and the absolute configuration was determined by comparing the optical rotation with literature values c ee %vas measured by comparing the optical rotation ith literature d. ee was measured HPLC using a Chtrace! OJ column.

Ruthenium complexes with chiral phosphines are excellent catalysts for the asymmetric hydrogenation of beta keto-esters. Table 1 1 lists the results based on Ru- BΪCP catalystic system.

TABLE 1 1 Asymmetric Hydrogenations of beta-Keto ester

o o Catalvst OH 0

^{^} OMe

MeOH "^ ^" O e

Entry Temp Catalyst H _: Pressure Con. % % ee

1 65 °C Ru(BiCP)Br2 1 atm 97 82

_o 40 »c u(BiCP)Br2 5 atm 95 76

., 50 °C Ru(BiCP)Ci2 5 atm 43 84

EXAMPLES

Unless otherwise indicated, all reactions were carried out under nitrogen. THF and ether were freshly distilled from sodium benzophenone kety l. Toluene and 1 ,4- dioxane were freshly distilled from sodium. Dichloromethane and hexane were freshly distilled from CaH . Methanol was distilled from magnesium and CaH Reactions w ere monitored by thin-layer chromatography (TLC) analysis. Column chromatography was performed using EM silica gel 60 (230-400 mesh). ^! H NMR were recorded on Bruker ACE 200, WP 200, AM 300 and WM 360 spectrometers. Chemical shifts are reported in ppm downfield from tetramethylsilane with the solvent resonance as the internal standard (CDCI3, δ 7.26 ppm) ¹ C, ^, P and ^l H NMR spectra were recorded on Bruker AM 300 and WM 360 or Vaπan 200 or 500 spectrometers with complete proton decoupling Chemical shifts are reported in ppm downfield from tetramethylsilane with the solv ent resonance as the internal standard (CDCI3, δ 77.0 ppm). Optical rotation was obtained on a Perkin-Elmer 241 polaπmeter. MS spectra were recorded on a RATOS mass spectrometer MS 9 '50 for LR-EI and HR-EI. GC analysis were carried on Hel vett- Packard 5890 gas chromatograph with a 30-m Supelco β-DEX™ or r-225Dex™ column HPLC analysis were earned on Waters™ 600 chromatograph with a 25-cm CHIRALCEL OD column.

Example 1 (as depicted in Scheme 2 and Figure 8)

(1R, l 'R)-Bicyclopentyl-(2S, 2'S)-diol (3 in scheme 2) Compound 3 was synthesized by asymmetric hydroboration of bι-1-cyclopenten- lyl using (+)-monotsopinocampheylborane ((+)-IpcBH2) according to the literature procedure (Brown, H. C; Jadhav, P. ., Mandal, A. . J. Org. Chem. 1982, 47, 5074). The absolute configuration of the diol was assigned based on the asymmetric hydroboration of tπsubstituted olefins (e.g. methylcyclopentene) using (- ^t -)-IpcBH ₂ ' H NMR (CDCI3, 300 MHz) δ 4.04(br, 2 H), 3.84 (m, 2 H), 2.02 (m, 2 H), 1.66-1.22 (m, 10 H), 1.21 (m, 2 H); ¹³ C NMR δ 78.6, 52.2, 33.6, 29.2, 20.5; MS z 170 (M ^* . 0.35), 152, 134, 108 , 95, 84, 68; HRMS calcd for CιoHi8θ ₂ : 170.1307(M ^* ); found: 170.1315.

Example 2

(as depicted in Scheme 2 and Figure 8)

(}R,1 'R)-Bicyclopentyl-(2S,2 'S)-diol bis(methanesulfonate)

To a solution of (1 R, l'R)-bicyclopentyl-(2S, 2'S)-dιol (0.8 g, 4 65 mmol) and triethylamine ( 1.68 L, 12.09 mmol) in CHiCh (30 mL) was added dropwise a solution of methanesulfonyl chloπde (0.76 mL, 9 92 mmol) in CH2CI2 (2 mL) at 0°C. The reaction mixture was stirred at 0°C for 30 min. and at rt for 2 h, then quenched by saturated aqueous ammonium chloπde solution (25 L). The aqueous layer was extracted with CH ₂ CI2 (3x20 mL) and the combined organic solution was dπed over Na^SO . After evaporation of the solvent, a w hite solid was obtained, which was used directly for the next step. Η NMR (CDCh. 200 MHz) δ 5.01 (m, 2H), 3.04 (s, 6 H). 2.1 ~

(m. 2 H), 2.15- 1.65 (m, 10 H), 1 .43- 1.52 (m. 2 H), ^{1 3} C NMR δ 86.8. 48.2. 3S 4. 32.8. 27.4. 22.5.

Example 3 (as depicted in Scheme 2 and Figure 8)

(1R, l'R, 2R, 2'R)-l,l '-Bis(2-diphenylphosphino)cyclopentyl bisborane Diphenylphosphine (1.25 mL, 7.0 mmol) in THF (80 mL) was cooled to -~S°C To this solution, n-BuLi in hexane (4.1 mL. 6.6 mmol) was added via syπnge over 5 min. The resulting orange solution was warmed to rt and stirred for 30 min. After cooling the mixture to -78°C, ( lR,rR.2S.2'S)-l ,l'-bicyclopentyl-2.2'-diol bismesylate ( 1.01 g. 3.1 mmol) in THF (20 mL) was added over 20 min. The resulting orange solution was warmed to rt and stirred overnight. The white suspension solution was hydrolyzed with saturated aqueous H ₄ CI solution. The aqueous layer was extracted with CH ₂ C1 ₂ (2 x 20 mL). The combined organic solution was dried over anhydrous After removal of the solvents under reduced pressure, the residue was dissolved in CH ₂ CI ₂ (50 mL), then treated with BH3 THF ( 10 mL, 10 mmol) at rt and the mixture was stirred overnight. The reaction mixture was added to NH ₄ CI aqueous solution, and extracted with CHiCb (2 x 50 mL). The combined organic solution was dπed over anhydrous a ₂ SO ₄ . After evaporation of the solvent under reduced pressure, the residue was subjected to column chromatography on silica gel, eluting with

(2.3) affording the product as a white solid. Yield: 0.36 g (21 %) 'H-NMR (CDCh) δ 7 80-7 30 (m, 20 H, Ph), 2.55-2.35 (m, 2 H. CHP(BH ₃ )Ph ₂ ), 1 95-1.35 (m, 14 H, CH ₂ and CH). 1.7-0 5 (broad. 6 H, BH ₃ ) ^ ^l p.NMR (CDCh). δP = 17 5 (br). ¹³ C-NMR (CDCh) δ 133 43 (d, 2 ^j (PC) = 8 5 Hz, C _orτho ), 132.25 (d, 2j(PQ = 8.5 Hz, C _onho ). 132.08 (d, IJ(PH) = 50.0 Hz. C _φs0 ), 130 67 (d. ⁴ J(PC) = 2.1 Hz, C _pa ra), 130.57 (d, ⁴ J(PC = 2.1 Hz. Cpara), 129 71 (d, ⁱ J(PC) = 56.5 Hz, C _φS0 ), 128.39 (d, -'J(PC) = 9 4 Hz. C _mel3 ). 128.29 (d, ³ J(PC) = 9.1 Hz, C _meta ), 46.28 (dd. J(PC) = 2.1 and 4.8 Hz, C _u -), 36.26 (d. 'J(PC) = 30.6 Hz, C ₂ ,y), 31 19 (CH ₂ ). 29.52 (CH ₂ ), 22.51 (CH ₂ ); MS m/z 520 (8.95). 506 (3 55), 429( 19 10), 321( 100), 253(7 45), 185(26 64), 108(43 68), 91 ( 1 1 99 ). "7(6 88). HRMS cacld for C ₂ sH ₃ i P ₂ (M--B ₂ H ₆ -Ph): 429.1901 , found 429.1906

Example 4 (as depicted in Scheme 2 and Figure 8) (2R, 2'R)-Bis(diphenylphosphino)-(lR, l 'R)-dicyclopentane (I) To a solution of teh above borane complex of the phosphine (0.24 g, 0 45 mmol) in CH ₂ C1? (4.5 mL) was added tetrafluoroboπc acid-dimethyl ether complex (0.55 mL. 4.5 mmol) dropwise via syringe at -5 °C. After the addition, the reaction mixture was allowed to warm slowly to rt, and stirred for 20 h. The mixture was diluted with CH ₂ Cb. and neutralized with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with CH ₂ Cb. The combined organic solution was washed with bπne. followed by water, and dπed over Na ₂ SO4. Evaporation of the solvent gave the pure phosphine Yield: 0.21 g (93%). ^! H NMR (CDCh. 360 MHz) δ 7.52-7 27 (m, 20 H), 2.53 (m, 2 H ). 2.27 (m. 2 H), 1.93(m. 2 H), 1.72(m, 2 H), 1.70- 1 43 (m. 8 H); ¹³ C NMR (CDCh) δ 139- 127 (Ph), 45.9 (d, J = 12.1 Hz), 45.8 (d, J = 12.0 Hz), 40.34 (d, J = 14.0 Hz), 30.9 (m). 23 8 (m); ^{3 1} P NMR (CDC1 ₃ ) δ -14.6 This phosphine was fully characteπzed by its borane complex.

Example 5 General Procedure for Asymmetric Hydrogenation

To a solution of [Rh(COD) ₂ ]BF (5.0 mg, 0.012 mmol) in THF ( 10 mL) in a glovebox was added chiral ligand 1 (0.15 mL of 0.1 M solution in toluene, 0.015 mmol). and E.3N (0.087 mL, 0.62 mmol). After stirring the mixture for 30 min. the dehvdroamino acid ( 1.2 mmol) was added. The hydrogenation was performed at rt under 1 atm of hydrogen for 24 h. The reaction mixture was treated with CH ₂ N . then concentrated in Vacuo. The residue was passed through a short silica gel column to remove the catalyst. The enantiomeric excesses were measured by GC using a Chirasil- V.AL III FSOT column. The absolute configuration of products was determined by compaπng the observed rotation with the reported value. All reactions went in quantitative yield with no by-products found by GC.

Example 6 (as depicted in Scheme 5 and Figure 12) (IR, 2S, 4R, 5S)-(+)-2,5-Dimethyl-7-phenyl-7-phosphabicyclo/2.2.1 /heptane borane (5) To phenylphosphine (3.0 ml, 27.3 mmol) in THF (200 mL) was added n-BuLi (34.5 mL of a 1.6 M solution in hexane, 55 mmol) via syringe at -78°C over 20 min. Then the orange solution was warmed up to rt and stirred for 1 hr at rt. To the resulting orange-yellow suspension was added a solution of ( 15,25,4.S',55)-2,5-dimethyl- cyclohexane- l ,4-diol bis(methanesulfonate) (3, 8.25 g, 27.5 mmol) in THF ( 100 mL) over 15 min. After the mixture was stirred overnight at rt, the paie-yeilow suspension was hydrolyzed with saturated NH4CI solution. The mixture was extracted with ether (2 x 50 mL), and the combined organic solution was dried over anhydrous sodium sulfate. After filtration , the solvents were removed under reduced pressure. The residue was dissolved in methylene chloride (100 mL), treated with BH3 THF (40 L of a 1.0 M solution in THF, 40 mmol) and the mixture was stirred overnight. It was then pured into saturated NH ₄ CI solution and extracted with CH ₂ C1 ₂ (3 x 50 mL). The combined organic solution was dried over anhydrous Na SO ₄ and filtered, the solvent was removed on reduced pressure. The residue was subjected to chromatography on silicon gel column, eluted w ith hexanes/CH ₂ CI ₂ (4: 1 ) affording the product as a white solid. Yield: 1.95 g (31 %). [ ]- ⁵ _D

= - 59.5° (c 1.07, CHC] ₃ ). ' H-NMR (CDC1 ₃ ) δ 7.60-7.30 ( . 5 H. C ₆ H ₅ ), 2.60-2.40 ( , 2 H, CHP(BH ₃ )Ph), 2.15-2.05 (m, 1 H. CH), 2.04- 1.80 (m, 4 H, CFb), 1 .65- 1.50 (m. 1 H. CH), 1.32 (d, ³ J(HH) = 6.5 Hz, 3 H. CH3), 0. 59 (d, ³ J(HH) = 6 7 Hz, 3 H, CH3), 1 .6-0.2 (br. BH ₃ ); ^l -'C-NMR (CDCI3) δ 13 1 .74 (d, ² J(PC) = 7.3 Hz. C _oπh o), 130.56 (d. Ij(PC) = 43.9 Hz, C _ιpso ), 129.92 (d, J(PC) = 2.0 Hz, C _pa r _a ), 128.44 (d, ³ J(PC) = 8.6 Hz, C _mcla ). 43.07 (d, ^l J(PC) = 30.5 Hz, CHP(BH ₃ )Ph), 40.85 (d, 'J(PC) = 31.6 Hz, CHP(BH Ph). 36.27 (CH ₂ ), 36.67 (d, ³ J(PC) = 13.5 Hz, CH ₂ ), 35.91 (d, ² J(PC) = 3.5 Hz, CH), 34.65 (d. J(PC) - 9.8 Hz, CH), 20.78 (CH3 20.53 (CH ₃ ); ³ lP-NMR (CDCI3) δ 36.3 (d. broad. 'J(PB) = 58.8 Hz); HRMS Calcd for C H ₂₂ BP: 232.1552 (M~); found: 232. 1578; C ₁₄ H ₁₉ P: 218.1224 (M"-BH ₃ ); found: 218.1233.

Example 7

(as depicted in Scheme 5 and Figure 12)

(IR, 2R, 4R, 5R)-(+)-2,5-Diisopropyl-7~phenyl-7-phosphabicγclo{2.2.1 /heptane borane

(6) Using the same procedure as in the preparation of 5. Yield: 0.33 g (50%). [ ] ²⁵ o

= - 25.5° (c 1.02, CHCh). ¹ H-NMR (CDCI3) δ 7.55-7.30 (m, 5 H. C ₆ H5), 2.85-2.70 9 (m.

2 H CHP(BH ₃ )Ph), 2.30-2.20 (m, 1 H, CH), 2.18-2.00 (m, 1 H, CH), 1.95-1.65 (m. 4 H.

CH2), 1.40-1.20 ( , 2 H, CH), 1.03 (d, ³ J(PH) = 6.5 Hz, CH3), 0.S7 (d, ³ J(PH) = 6.7 Hz.

CH ₃ ), 0.85 (d, J(PH) = 7.4 Hz, CH3), 0.53 (s, broad, 3 H, CH ), 1.5-0.2 (broad. BH ₃ ); ¹³ C-NMR (CDCh,) δ 131.19 (d, ² J(PC)= 8.3 Hz, C _oπ ho), 130.71 (d, ^(PC) = 45.2 Hz.

C _ιpso ), 129.97 (d, J(PC) = 2.5 Hz, C _para ), 128.45 (d, ³ J(PC) = 9.5 Hz, C _meU ), 50.30 (d.

-J(PC) = 2.1 Hz, CH), 48.77 (d, ² J(PC) = 9.7 Hz, CH), 38.2" (d, *J(PC) = 30.5 Hz.

CHP(BH ₃ )Ph), 36.81 (CH ₂ ), 36.71 (d, ^l J(PC) = 31.5 Hz. CHP(BH3)Ph), 34.73 (d.

³ J(PC) = 13.7 Hz, CH ₂ ), 31.92 (CHMe ₂ ), 31.12 (CHMe ₂ ), 22.41 (CH ₃ ), 21.55 ( CH ₃ ). 20.73 (CH3), 20.10 (CH ₃ ); ^{3 1} P-NMR (CDCI3) δ 36.d (d, broad. 'J(PB) = 51.4 Hz).

Example 8 (as depicted in Scheme 5 and Figure 12) (IR. 2S, 4R, 5S)-(+)-2,5-Dimethyl-7-phenyl-7-phosphabicyclof2.2.1 /heptane (40) To a solution of corresponding borane complex of the phosphine (5, 1 0 g, 4 3 1 mmol) in CH ₂ C1 (22 mL) was added tetrafluoroboric acid-dimethyl ether complex (2.63 mL. 21.6 mmol) dropwise via a syringe at -5 °C. After the addition, the reaction mixture was allow ed to warm up slowly, and stirred at rt. After 20 h, ^{3 1} P NMR showed the reaction was ov er, it was diluted by CH ₂ C1 ₂ , neutralized by saturated NaHCO} aqueous solution The aqueous layer was extracted with CH ₂ Cb The combined organic solution was washed with bπne, followed by water, and then dπed ov er Na Sθ ₄ . Evaporation of the solvent gave a pure phosphine product, which was confirmed by NMR. Yield 0.9 e (96%). [α] ²⁵ _D = -92.5° (c 2.3, toluene); ^! H NMR (CDCh, 360 MHz) δ 7.38- ^{^} 34 (m. 2H), 7.26-7.21 (m, 2H), 7.19-7 16 (m, 1H), 2.60-2.54 (m, 2H), 1 89-1.62 (m. 5H), 1.44- 1.42 (m, 1 H), 1.16 (d, J = 6.12 Hz, 3H), 0.55 (d, J = 6.95 Hz. 3H); ^C NMR (CDCh) ό 138.68 (d, J = 29.3 Hz), 131.42 (d, J = 13.0 Hz), 127.88 (d, J = 2.35 Hz), 126.57 (s). 47.34 (d. J = 13.5 Hz), 45 26 (d, J = 10.2 Hz), 39.21 (d, J = 6.7 Hz), 39 21 (d, J = 5 3 Hz). 38.74 (d, J = 6.7 Hz), 34.69 (d, 17.2 Hz), 22.37 (d, J = 7 8 Hz), 21.52 (s), 31 p NMR(CDCh) δ -7.29.

Example 9 (as depicted in Scheme 5 and Figure 12)

(IR, 2R, 4R, 5R)-(+)-2,5-Diisopropyl-7-phenyl-7-phosphabicyciof2.2.1/hept ane

(8 in scheme 5) Using the same procedure as in the preparation of 7 Yield: 1 0 g (95.5%) [α] ²⁵ o = +43.9° (c 1.2, toluene); ^l H NMR (CDC1 ₃ , 360 MHz) δ 7.35-7 30 (m. 2H), ~.24-7 14 (m, 3H), 2.94-2.85 (m, 2H), 1.76-1.53 (m, 5H), 1.25-1.14 (m. 2H), 1.06 (d, J = 7 77 Hz. 3H), 0.95-08.0 (m, 1 H), 0.87 (dd, J = 3.77 Hz, 7.89 Hz. 6 H), 0 49 (d, J = 9.30 Hz, 3H); ¹³ C NMR (CDCI3) δ 138.83 (d, J = 30.49 Hz), 130.69 (d, J = 12.2 Hz), 127 "1 (d, J = 2.87 Hz), 126.45 (s), 53.38 (d, J = 6.34 Hz), 48.63 (d, J = 17 06 Hz), 41 97 (d. J = 13 43

Hz), 40 51 (d, J = 9 96 Hz), 37 60 (d. J = 1 1 09 Hz), 37 39 (d, J = 9 74 Hz), 33 03 (d, 6 1 1 Hz), 31 86 (s), 21 89 (s), 21 78 (s), 21 23 (s), 20 40 (s), ^{3 1} P NMR(CDCh) δ -7 49

Example 10 Enantioselechve Allylic Alkylation The procedures are exemplified by the expeπments arned out w ith ligand 7 in toluene To a stirπng solution of [Pd ₂ (η ³ -C ₃ Hs) ₂ Ch] (3 0 mg, 0 008 mmol) in toluene ( 1 5 L) was added ligand 7 (0 36 mL of 0 1 M solution in toluene. 0 036 mmol) under a nitrogen atmosphere After 30 mins, racemic 1 ,3-dιphenyl-l -acetoxypropene ( 150 mg, 0 60 mmol) was added Then the solution was allowed to be stirred 30 ins N,0- bιs(tπmethylsιyl)acetamιde (0 44 mL, 1 8 mmol), dimethyl malonate (0 21 mL, 1 8 mmol) and potassium acetate (3 mg. 0 03 mmol) were added in this order The reaction w as monitored bv TLC (eluent Hexane / ethy l acetate = 10/1 ) λfter 1 5 hrs, TLC showed the reaction was over After the solvent was evaporated in vacuo, column chromatography on silica gel (eluent Hexane / ethyl acetate = 10/1 ) of the residue yielded the pure product Yield 190 mg, 97 7% The optical pun ty was determined to be 95 5% ee by HPLC (Daicel Chiralcel OD column, 1 ml/mm. hexane 2-propanoi = 99/1 )

Example 11 Typical Procedure for Hydrogenation oflmines To a solution of chloro(l ,5cyclooctadιene)indιum(I) dimer (2 mg, 0 003 mmol) in toluene (4 mL) was added a solution of BICP in toluene (0 1 M, 71 ul, 0 0071 mmoi), the resulting solution was stirred in glovebox for 30 min Then phthalimide (3 5 mg, mmol) was added and the reaction mixture was stirred for another 30 m before 2,3,3- tnmethyhndolenine (96 ul, 0 6 mmol) was added The reaction tube was placed in an autoclave, pressuπzed with hydrogen to l OOOpsi after several exchange w ith hydrogen, and stirred at rt for 65 h Conversion (97 8%) and enantiomeπc excess (92 2%) were determined by GC (a capillary column γ-dex-225)

Example 12

(as depicted in Scheme 3, Figure 5 and Figure 1 1 )

Me-PennPhos: l,2-Bis{(lR,2S,4R,5S)-2,5-dimethyl-8-phenylphospha- bicyclo/2.2. l/heptyljbenzene (36a) To the suspension of NaH (8 0 g, 333 mmol) in THF (200 ml), cooled to O 'C, was added 1.2-dιphosphιnobenzene (4 0 ml, 30 4 mmol), followed by HMPA (80 ml) The resulting orange suspension was stirred at 0°C for 1 h ( lS,2S,4S.5S)-2,5- dιmethylcyclohexane-l ,4-dιol dimesolate (18 3 g, 60 9 mmol) in THF ( 150 ml) was added over 20 min The resulting orange-red suspension was stirred at RT for 3 5 days. hvdrolyzed with NaCl-H O and then extracted ith hexane (2 x 100 ml) The combined organic solution w as dπed over Na ₂ SO After filtration, the solvents w ere remov ed under reduced pressure. The residue was subjected to chromatography on silica gel column, eluted with hexane Yield. 3 0 g (27.5%) 'H-NMR (CDC1 ₃ ) δH = 7 25-7 10

(m, 2 H, aromatic), 7.08-6.95 (m, 2 H, aromatic), 3.21 (d, broad, 2 H, ² J(PH) = 14 5 Hz. PCH), 2.58 (d, broad, 2 H, J(PH) = 13.4 Hz, PCH), 1.90-1 60 (m, 12 H), 1 55-1 35 (m. 2

H,), 1 17 (d, 6 H, ³ J(HH) = 6.3 Hz, CH ₃ ), 0.60 (d, 6 H, ³ J(HH) = 6 3 Hz. CH3). CH ' ³ C-

NMR (is out of first order, CDCI3) δC = 143.94, 143 66, 143 48, 143.20, 131 05. 131.00.

130.93, 126.33, 46,24, 46.20, 46, 17, 46.13, 45.92, 45.69, 45 61 , 45 38, 40 17, 40.05.

39.89, 39 73, 39 61 , 39.52, 39.33, 39.29, 39.26, 34.76, 34 61. 34 51, 34 41 , 34 26. 22.69. 22.65, 22 61 , 20.82. ³¹ P-NMR (CDCI3). δP = -7.3 ppm.

Example 13 (as depicted in Scheme 3 and Figure 11) i-Pr-PennPhos: l,2-Bis{(lR,2R,4R,SR)-2,5-bis-isopropyl-8-phenylphos- phabicyclo[2.2. l/heptyl}benzene (36b) 1 ,2-dιphosphinobenzene (0.4 ml, 3 04 mmol) and NaH (0 9 g. 37 5 mmol) were mixed in THF (50 ml) and cooled to 0°C. HMPA (8 5 ml, 49 mmol) was added The resulting orange suspension was stirred at 0°C for 1 h and then ( lS,2S,4S.5S)-2.5- dimethyl-cyclohexane- 1 ,4-dιol dimesolate (2.17 g, 6.08 mmol) in THF (40 ml) as added over 10 min. The resulting orange-red suspension was stirred at RT for 3 day s After cooled to 0°C, it was hvdrolyzed with NaCl-H ₂ O, and extracted with hexane (2 \ 50 ml)

O 97/47633

The combined organic solution was dried over Na SO ₄ and filtered. The solvents were removed under reduced pressure. The residue was subjected to chromatography on silica gel column, eluted with hexane. Yield: 0.6 g (42%). ' H-NMR (CDCI3): δH = 7.20-7.10 (m. 2 H, aromatic), 7.05-6.90 (m, 2 H, aromatic), 3.38 (d, broad, 2 H, ² J(PH) = 14.2 Hz, PCH), 2.85 (d, broad, 2 H, ² J(PH) = 13.5 Hz, PCH), 1.85- 1.45 (m, 12 H). 1.30- 1 .08 (m, 4 H), 1.03 (d, 6H, ³ J(HH) = 6.4 Hz, CH ₃ ), 0.96 (d, 6H, ³ J(HH) = 5.6 Hz. CH ₃ ), 0.86 (d, 6H, ³ J(HH) = 6.5 Hz, CH3), 0.47 (s, 6 H, CH3). ¹³ C-NMR (is out of first order, CDCI3): δC =

143.97, 143.62, 143.56, 143.50, 143.45, 143.09, 130.96, 130.90, 130.86, 126.1 1 , 54.10, 54.06, 54.03, 48.65, 48.56, 48.46, 42.02, 41.96, 41.24, 41.20, 41.18, 41.14, 37.94, 37.77, 37.60, 37.46, 33.29, 33.27, 33.24, 31.69, 23,45, 23.40, 23.35, 22.22. 20.97, 20.54. 31p. NMR (CDCI3): δP = -8.7 ppm.

Example 14

(as depicted in Scheme 4, Figure 4 and Figure 10)

C5- Tricyctophos: l,2-Bis{(2R, 6R, 7R, 1 lR)phosphatricyclo[3.3.0. OJundecanylj-benzene (26)

1 ,2-diphosphinobenzene (0.20 ml, 1.52 mmol) and NaH (0.40 g, 16.7 mmol) were mixed in THF (50 ml) and cooled to 0°C. HMPA (4.3 ml, 25 mmol) was added. The resulting orange suspension was stirred at 0°C for 1 h and then treated with (lR,rR,2S,2'S)-l,r-bicycIopentyl-2,2'-diol bismesylate (0.993 g, 3.04 mmol) in THF (40 ml). The resulting orange-red suspension was stirred at RT for 20 h, pale orange-yellow suspension formed. After cooled to 0°C, it was hydrolyzed with NaCl-H O, and extracted with hexane (2 x 50 ml). The combined organic solution was dried over Na ₂ SO ₄ and filtered. The solvents were removed under reduced pressure. The residue was subjected to chromatography on silica gel column, eluted with hexane/ether (40: 1.5). Yield: 0.42 g (67%). > H-NMR (CDCI3): δH = 7.50-7.30 (m, 2 H, aromatic), 7.25-7.10 (m, 2 H, aromatic), 3.15-2.95 (m, 2 H, PCH), 2.85-2.70 (m, 2 H, PCH), 2.50-2.30 (m, 4 H, CH), 2.05-1.00 (m, 24 H, CH ₂ ). ¹ C-NMR (is out of first order, CDCI3): δC = . 144.03,

143.98, 130.16, 130.12, 130.08, 127.50, 53.64, 52.97, 44.72, 44.66, 44.60, 43.07. 32.64, 32.01 , 31.86, 31.68, 30.58, 26.47, 25.41, 25.36, 25.31. ^{3 l} P-NMR (CDCh): δP = 9.6 ppm.

Example 15 General Procedure for Asymmetric Hydrogenation of Dehydroaminoacids for

Pennphos ligands

In a glovebox. a schlenk reaction bottle was charged with a giv en amount of Rh catalyst precursor and Me-PennPhos in a ratio of 1.1 mol ligand per 1 mol Rh and 10 ml of the given solvent (dπed and degassed), the resulting orange-yellow solution was stirred at rt for 20 min. Then substrate ( 1 mmol, sub/cat = 100) was added. The nitrogen atmosphere was exchanged to H ₂ by flashing the schlenk w ith H ₂ . The reaction mixture was then stirred at RT and 1 atm H ₂ for a certain peπod of time. The reaction solution was passed through a short silica gel, washed with ether. The conversion and ee were measured by GC analysis on Chirasil-Val III column. The absolute configuration was determined by measuπng the rotation of product and compaπng w ith the corresponding standard values.

Example 16 General Procedure for Asymmetric Hydrogenation of Ketones

In a glovebox, a reaction bottle was charged with [Rh(COD)Cl] (2.5 mg, 0.0101 mmol) and Me-PennPhos (3.7 mg, 0.0103 rnmol), and MeOH ( 10 ml. dπed and degassed), the resulting orange-yellow solution was stirred at rt for 30 m . Then ketone substrate ( 1 mmol. substrate /catalyst = 100) was added. The reaction solution w as then piaced in an autoclave. The nitrogen atmosphere was exchanged to H ₂ by flashing the autoclave with H ₂ ( 10 to 20 atm). The autoclave was pressurized to a certain atmosphere of H ₂ The reaction mixture was then stirred at RT for a given peπod of time. The reaction solution was then passed through a short silica gel, washed with ether The conversion and ee were measured by GC analysis on chiral β-dex 120 column. The absolute configuration was determined by measuπng the rotation of product and comparing with the corresponding standard values.

Example 17 General Procedure for Asymmetric Hydrogenation of beta-Keto esters

BICP (0.01 mol) and Ru(COD)(2-methylallyl), (0.01 mol) were placed in a 10 ml Schlenk tube and the vessel was purged with argon. 2 mL of anhydrous acetone were added To this suspension was added methanolic HBr (0.1 1 ml of a 0.29 M solution) and the suspension was stirred 30 min at rt. The solvent was thoroughly evaporated under vacuum and the Ru(BICP)Br obtained vvas used immediately The solution of appropriate substrate (1 mmol) in degassed solvent (2 ml) was placed in a 10 ml Schlenck tube and degasses by 3 cycles of vacuum argon. This mixture was added to the catalyst ( 1%) in a glass vessel and placed under argon in 300 ml stainless steel autoclav e The .Argon atmosphere was replaced with hydrogen. The hydrogenations were run under the reaction conditions given The solvent was removed under pressure. Conversion and ee are determined by chiral GC column β-dex 120 and γ-dex 225.

The above examples illustrate the present invention and are not intended to limit the invention in spiπt or scope.

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