(η4-1,5-CYCLOOCTADIENE)(1-[(4S)-(2-(1-ADAMANTYL)-4,5-DIHYDROOXAZOLYL)ETHYL] 1

(η4-1,5-Cyclooctadiene)(1-[(4S)-(2-(1-adamantyl)-4,5-dihydrooxazolyl)-ethyl]-3-(2,6-diisopropylphenyl)imida-zolin-2-ylidene)iridium(I) Tetrakis(3,5-bis(trifluoromethyl)phenyl)borate and(η4-1,5-Cyclooctadiene)(1-[(4R)-(2-(1-adamantyl)-4,5-dihydrooxazolyl)ethyl]-3-(2,6-diisopropylphenyl)imidazolin-2-ylidene)iridium(I) Tetrakis(3,5-bis(tri-fluoromethyl)phenyl)borate

iPr

iPr

NO

IrN

N

BARF–

(COD)

(S)-Cat

+

(S)-Cat[369657-31-8] C70H65BF24IrN3O (MW 1623.3)InChI = 1S/C32H12BF24.C30H41N3O.C8H12.Ir/c34-25(35,

36)13-1-14(26(37,38)39)6-21(5-13)33(22-7-15(27(40,41)42)2-16(8-22)28(43,44)45,23-9-17(29(46,47)48)3-18(10-23)30(49,50)51)24-11-19(31(52,53)54)4-20(12-24)32(55,56)57;1-20(2)26-6-5-7-27(21(3)4)28(26)33-11-10-32(19-33)9-8-25-18-34-29(31-25)30-15-22-12-23(16-30)14-24(13-22)17-30;1-2-4-6-8-7-5-3-1;/h1-12H;5-7,10-11,20-25H,8-9,12-18H2,1-4H3;1-2,7-8H,3-6H2;/q-1;;;+1/b;;2-1-,8-7-;/t;22-,23+,24-,25-,30-;;/m.0../s1

InChIKey = JAXAMUMADTUKIB-GZFVFXHHSA-N

iPr

iPr

NO

IrN

N

BARF–

(COD)

(R)-Cat

+

(R)-Cat[934621-83-7] C70H65BF24IrN3O (MW 1623.3)InChI = 1S/C32H12BF24.C30H41N3O.C8H12.Ir/c34-25(35,

36)13-1-14(26(37,38)39)6-21(5-13)33(22-7-15(27(40,41)42)2-16(8-22)28(43,44)45,23-9-17(29(46,47)48)3-18(10-23)30(49,50)51)24-11-19(31(52,53)54)4-20(12-24)32(55,56)57;1-20(2)26-6-5-7-27(21(3)4)28(26)33-11-10-32(19-33)9-8-25-18-34-29(31-25)30-15-22-12-23(16-30)14-24(13-22)17-30;1-2-4-6-8-7-5-3-1;/h1-

12H;5-7,10-11,20-25H,8-9,12-18H2,1-4H3;1-2,7-8H,3-6H2;/q-1;;;+1/b;;2-1-,8-7-;/t;22-,23+,24-,25-,30-;;/m.1../s1

InChIKey = JAXAMUMADTUKIB-QSOYDDQHSA-N

(chiral homogeneous catalysts for asymmetric hydrogenation,especially of hindered and highly substituted, unfunctionalizedalkenes; useful in diastereoselective hydrogenation of variouschiral alkenes; catalysts for acid-sensitive alkenes like alkyl

enol ethers)

Physical Data: orange solid.Solubility: sol most common organic solvents; insol water.Form Supplied in: not currently commercially available.Analysis of Reagent Purity: 1H NMR, 13C NMR, elemental

analysis.Preparative Methods: the NHC-oxazoline bidentate ligand is de-

rived from an imidazolium salt, which is easily handled, ro-bust, and air stable. This salt is obtained from an oxazolineelectrophile and an imidazole (eq 1). The catalyst Cat can bemade from the salt by reacting with an iridium precursor andexchanging the anion of the complex formed with tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (BARF−) (eq 2).1 Both (R)-Cat and (S)-Cat can be made through the same route, startingfrom enantiomers of dimethyl aspartate, both of which are com-mercially available.

N

I

O

AdN N

DMF

100 oC, 12 hquantitative

yield

+

(1)

iPr

iPr

iPr

iPrN

O

N

N+

Ad

I–

Ad

IrN

Ar

NN

O

NAr N+

AdO

N

+

BARF–I–

1. [Ir(COD)Cl]2, LiOtBu

THF, 70 oC, 16 h

64%

(2)2. NaBARF 1:1 H2O:CH2Cl2

Ar =iPr

iPr

Ad =

Purification: flash chromatography.Handling, Storage, and Precautions: the catalysts are sufficiently

stable to be handled in air. The catalyst might deactivate rapidlyif exposed to H2 in the absence of substrates, so mixing ofthe substrates with the catalyst prior to the addition of H2 is

2 (η4-1,5-CYCLOOCTADIENE)(1-[(4S)-(2-(1-ADAMANTYL)-4,5-DIHYDROOXAZOLYL)ETHYL]

recommended. Catalytic activities in this series tend to be re-duced by coordinating solvents (e.g., THF and traces of water).Use of dry noncoordinating solvents (e.g., CH2Cl2 or MePh) isrecommended.

Asymmetric Hydrogenation of Unfunctionalized Alkenes.Crabtree’s catalyst in the hydrogenation of unfunctionalizedalkenes2,3 inspired Pfaltz and coworkers to prepare and testiridium complexes with chiral oxazoline phosphine bidentate lig-ands in asymmetric hydrogenation of trisubstituted alkenes with-out functional groups (mostly styrene and stilbene derivatives).Near-perfect conversions and enantiomeric excesses up to 99%were obtained.4,5 Hindered (tri- and tetrasubstituted) alkenes arehydrogenated in the presence of bisphosphine catalysts only ifthere is a proximal coordinating functional group (CFG).Chiral analogs of Crabtree’s catalysts can mediate hydrogenationsof alkenes without an obvious CFG, hence they are applicable to abroad range of substrates. This reflects an important difference be-tween reactivities for chiral analogs of Crabtree’s catalyst (cationicIr with an N,P ligand set or similar) and Wilkinson’s catalyst (Rh,Ir, Ru bisphosphine complexes).

+

PCy3

Ir

N

PF6–

Crabtree’s catalyst

+

P

Ir

N

O

BARF–

Ar2

tBu

Pfaltz’s catalyst

Cat was the first complex of a N-heterocyclic carbene (NHC)ligand to give high enantiomeric excesses in any reaction;6 the pre-vious best was a palladium-mediated intramolecular cyclizationthat gave 76% ee.7 In the first applications of Cat, excellent enan-tioselectivities (up to 98% ee) were achieved for (E)-trisubstitutedalkenes (eq 3). Isomeric (Z)-alkenes gave significantly lower con-versions and enantioselectivities (usually 58–99% conversion,8–79% ee). Hydrogenations of 1,1-disubstituted alkenes wereachieved with up to 89% ee and 100% conversion using Cat at1 bar H2 pressure at 25 ◦C.1

Ar

R1

R250 bar H2, 0.006 Cat

Ar

R1

R2

Ar = Ph, 4-MeO-C6H4, 2-naphthylR1 = Me; R2 = Ph, Me, iPr, CH2OH

conv 90–99%93–98% ee

CH2Cl2, 25 oC, 2 h(3)

Asymmetric Hydrogenation of Unfunctionalized Aryl-substituted Dienes. Asymmetric hydrogenations of dienescan generate two or more chiral centers; control of relative andabsolute stereochemistry in this process had not been investigatedprior to reactions with Cat. Still, little is known about asymmetrichydrogenations of conjugated dienes of any kind,8–10 thoughsubsequent to this work, Pfaltz has a notable success with non-conjugated dienes.11 Using Cat, selectivities up to 20:1 dr and

99% ee were achieved. Thus, hydrogenation of (E,E)-1,4-diaryl-1,4-dimethyl-1,3-butadienes gave high conversions and stereo-selectivities (eq 4). Enantioselectivities for the hydrogenation of(E,E)-1,4-diaryl-2,3-dimethylbuta-1,3-dienes were excellent(97–99% ee) but the yields were moderate because of formationof double bond migration by-products (eq 5). Dienes containing1,1-disubstituted alkene fragments gave lesser stereoselectivities(eqs 6 and 7), and sometimes meso products were formed in pref-erence to the corresponding optically active compounds (eq 6).Higher conversions and yields were observed from Cat than fromCrabtree’s catalyst in these reactions.12 The rhodium analog ofCat was unreactive in these reactions.13

50 bar H2, 0.02 (S)-Cat

(4)

ArAr

ArAr

ArAr+

ent meso

Ph 92 98 14:1.0 4-methyl phenyl 100 99 20:1.0 5-methyl-2-furanyl 100 70 1.2:1.0

yield % ee % ent/mesoAr

CH2Cl2, 25 oC, 24 h

50 bar H2, 0.01 (S)-Cat

(5)

ArAr

ArAr

ArAr+

ent meso

Ph 69 98 1.3:1.03-methyl phenyl 67 97 1.3:1.05-methyl-2-furanyl 96 99 1.8:1.0

yield % ee % ent/mesoAr

CH2Cl2, 25 oC, 2 h

10 bar H2, 0.01 (S)-Cat

(6)

PhPh

PhPh

PhPh+

ent meso

65 24 1.0:2.9

yield % ee % ent/meso

PhMe, 25 oC, 2 h

(η4-1,5-CYCLOOCTADIENE)(1-[(4S)-(2-(1-ADAMANTYL)-4,5-DIHYDROOXAZOLYL)ETHYL] 3

10 bar H2, 0.01 (S)-Cat

(7)

PhPh

PhPh Ph

Ph+

ent meso

yield % ee % ent/meso

CH2Cl2, 25 oC, 24 h

100 86 2.1:1.0

Asymmetric Hydrogenation of Alkyl Vinyl Ethers. Alkylenol ethers are more acid-sensitive than vinyl acetates. The lat-ter substrates have CFGs (the acetate) and can be hydrogenatedwell with many M-diphosphine catalysts. However, alkyl vinylethers do not have obvious CFGs, hence they are more difficultsubstrates for asymmetric hydrogenations. Andersson14 had ex-plored the asymmetric hydrogenation of a simple vinyl ether byusing his N,P-Ir catalysts and observed formation of complexmixtures for those reactions. When Cat was used for hydrogena-tion of vinyl ethers, the reactions proceeded without formationof by-products giving enantiomeric excesses up to 98%.15 Lessacid-sensitive enol ether esters 1, with 1 mol % Cat, were hydro-genated to completion in 48 h giving up to 88% ee (eq 8). Forthe more acid-sensitive enol ether alcohols 2, the same reactionconditions gave significant amounts of by-products via an acid-catalyzed elimination–enone formation–hydrogenation process.However, the reaction gave the direct hydrogenation product if anappropriate amount of K2CO3 was added. The reaction was fasterand more enantioselective for the enol ether alcohols 2 (eq 9).

(8)R1O

O

OR2

50 bar H2

0.01 (S)-Cat

OR1 O

OR2

85–99% convup to 88% ee

(1)

R1 = Me, Et; R2 = Me, Et, tBu

CH2Cl225 oC, 48 h

R1 = Me, iPr, nBu; R2 = Me, Et; R3 = H, Ac, TBDPS

(9)R2O

R1 OR3 50 bar H2 0.01 (S)-Cat

R1

OR2 OR3

>99% convup to 98% ee

(2)1 equiv K2CO3, CH2Cl2

25 oC, 12 h

The data described above imply that protons were produced inthe hydrogenation reactions. They also indicate that N,P-Ir cata-lyst precursors generate more acid than the corresponding carbenecatalyst (cf. the N,P-Ir complexes seemed to cause more decom-position). DFT calculations and data from several different typesof experiment supported this postulate.16 Specifically, the DFTcalculations indicate an acidity difference of 7 pKa units betweenpostulated Ir(5+)H4 species,17,18 with the N,P-Ir complexes beingthe more acidic. These observations indicate that the Ir carbenecatalyst Cat may be well suited to acid-sensitive substrates.

Asymmetric Hydrogenation to Deoxypolyketide Chirons.

POFG

A

POFG

B

Chirons A and B can be used in syntheses of many deoxy-polyketides. Routes to chirons A and B can be segregated into‘diastereoselective reactions involving chiral auxiliaries’ and ‘cat-alytic methods’.19 Myers’ diastereoselective alkylation method-ology is probably the most practical of the first-generationmethods,20 but recent catalytic approaches are probably asusable.21,22 In 2007, Burgess and coworkers found that allylicalcohols and enoates bearing a stereogenic center adjacent to theC=C bond can be converted to precursors for syntheses of de-oxypolyketides. Hydrogenation of enoate 3 using (S)-Cat occurswith high diastereoselectivity (anti:syn 23:1.0; eq 10). An inverted(and lesser) diastereoselectivity was observed when the antipodeof the catalyst was used, hence this transformation is catalystcontrolled.23 The corresponding syn product was obtained withhigh selectivity when a different substrate, the Z-allylic alcohol 5,was hydrogenated using (R)-Cat (syn:anti 34:1.0; eq 11).24

(10)PO OMe

O 50 bar H2

0.002 CatPO OMe

O

(3)

P = TBDPS

(4)

(R)-Catsyn:anti

crude: 7.8:1.0 not purified

(S)-Catsyn:anti

crude: 1.0:23 purified: 1.0:40

90% isolated

CH2Cl225 °C, 4 h

(R)-Catsyn:anti

crude: 34:1.0 purified: 120:1.0

93% isolated

(S)-Catsyn:anti

crude: 1.0:3.4not purified

(11)

50 bar H2

0.002 Cat

P = TBDPS

PO

OH

PO OH

(5) (6)

CH2Cl225 °C, 4 h

The above work illustrates formation of 1,3-dimethylated chi-rons. Their higher homologs, 1,3,5-trimethylated chirons, weremostly obtained via diastereoselective hydrogenations of chiralalkenes derived from anti-4 and syn-6. However, in one case, ananti,syn chiron was obtained from direct hydrogenation of the chi-ral diene 10. Two chiral centers were generated in this reactionwith very good diastereoselectivity (eqs 12–15).24

4 (η4-1,5-CYCLOOCTADIENE)(1-[(4S)-(2-(1-ADAMANTYL)-4,5-DIHYDROOXAZOLYL)ETHYL]

(12)

50 bar H2, 0.01 CatTBDPSO OMe

O

TBDPSO OMe

O(7)

(R)-Catsyn:anti

crude: 1.0:12 purified: 1.0:120

70% isolated

(S)-Catsyn:anti

crude: 2.1:1.0not purified

CH2Cl2, 25 °C, 4 h

(13)

50 bar H2, 0.01 CatTBDPSO OMe

O

TBDPSO OMe

O(8)

(R)-Catsyn:anti

crude: 2.0:1.0 not purified

(S)-Catsyn:anti

crude: 1.0:15 purified: 1.0:89

82% isolated

CH2Cl2, 25 °C, 4 h

(R)-Catsyn:anti

crude: 12:1.0 purified: 120:1.0

71% isolated

(S)-Catsyn:anti

crude: 1.0:6.0not purified

(14)

50 bar H2, 0.01 CatTBDPSO

TBDPSO OH

(9)OH

CH2Cl2, 25 °C, 4 h

(R)-Catanti,syn:syn,syn purified: 51:1.0 83% isolated

(15)

50 bar H2, 0.01 CatTBDPSO OH

TBDPSO OH

(10)

syn,syn anti,syn syn,anti anti,anti

1.021

354.2

nd1.0

2.13.2

(R)-Cat(S)-Cat

CH2Cl2, 25 °C, 4 h

Asymmetric hydrogenation routes to deoxypolyketide frag-ments presented here are competitive with the state-of-the-art

methods in terms of catalyst loading, stereoselectivities, and atomeconomy. This methodology is practical: it has been used, for in-stance, in the preparation of (S,R,R,S,R,S)-4,6,8,10,16,18-hexa-methyldocosane.25

(S,R,R,S,R,S)-4,6,8,10,16,18-hexamethyldocosane

Asymmetric Hydrogenation to 1,3-Hydroxymethyl Chi-rons. All the substrates featured in the previous section werederived from Roche’s ester. However, several other readily avail-able natural starting materials could be used to generate relatedchirons in a similar way. This section features 1,3-hydroxymethylfragments as illustrated in eq 16.26

(16)

OH

C

OH

D

R = H or alkyl

terminalinternal

all stereoisomers possible

Ralkenes50 bar H2, 25 oC

iridiumcarbene-oxazoline

catalyst

or

Allylic alcohols 11 and 12 can be synthesized from glyceralde-hyde in a few steps with high enantiomeric purities. Hydrogena-tion of enoate 11 occurs with high diastereoselectivity (syn:anti19:1.0) when using (R)-Cat (eq 17). Substrate control in this reac-tion was observed, presumably because the homoallylic alcoholdirects the catalyst via a chair-like intermediate with the allylicsubstituent in an equatorial position.27 After hydrogenation, thecrude mixture was treated with catalytic acid to give the lactoneshown, which can be purified via recrystallization from ether in-creasing the dr to 40:1.0. To access the anti-stereochemistry ofchiron C with high selectivity, allylic alcohol 12 was hydrogenatedusing (R)-Cat to give the product with a syn:anti ratio of 1.0:24(eq 18); the dr of this product can be further improved by flashchromatography.

1. 50 bar H2, 0.01 Cat CH2Cl2, 25 °C, 4 h

HO

TBDPSO

OMe

O

(11)

>99% conv

O

O

OTBDPS

(R)-Catsyn:anti

crude: 19:1.0 purified: 40:1.0

75% isolated

(S)-Catsyn:anti

crude: 17:1.0not purified

(17)

2. TsOH, CH2Cl2 25 °C, 1 h

(η4-1,5-CYCLOOCTADIENE)(1-[(4S)-(2-(1-ADAMANTYL)-4,5-DIHYDROOXAZOLYL)ETHYL] 5

(18)PO

OH

OH

(12)

PO

OH

OH

(R)-Catsyn:anti

crude: 1.0:24purified: 1.0:56 84% isolated

(S)-Catsyn:anti

crude: 14:1.0not purified

50 bar H2

0.01 Cat

P = TBDPS

CH2Cl225 °C, 4 h

>99% conv

A similar approach to that shown above, but using lactic acid,was used to obtain optically pure syn- and anti-isomers corre-sponding to the terminal fragment D. Both isomers could be ob-tained with excellent diastereoselectivities and high yields; thiswas achieved by varying the substrate protection to optimize theoverall stereoselectivity (eqs 19 and 20). Hydrogenation of 13 wasonly marginally catalyst controlled, and substrate control domi-nated for 14. This is exceptional in the series of reactions reportedhere for Cat where catalyst control is the norm.

(19)

(13) (R)-Catsyn:anti

crude: 1.0:1.1not purified

(S)-Catsyn:anti

crude: 38:1.0purified: 78:1.0 68% isolated

50 bar H2

0.01 Cat

TBDPSO

OHTBDPSO

OHCH2Cl2

25 °C, 4 h>99% conv

(20)

(14)(R)-Catsyn:anti

crude: 1.0:55purified: >99% de

80% isolated

(S)-Catsyn:anti

crude: 1.0:7.3not purified

50 bar H2

0.01 Cat

OH

OTBDPSOH

OTBDPSCH2Cl2

25 °C, 4 h>99% conv

The synthesis of (−)-dihydromyoporone was performed toillustrate the hydrogenation methodology shown above. A morecomplex natural product (−)-spongidepsin was also synthesized;the latter compound contains both 1,3-dimethyl and 1,3-hydroxy-methyl fragments.28

OH

iPr

O

O

(–)-dihydromyoporone

asymmetric hydrogenationanti:syn 56:1.0

O

N

O

Ph

O

(–)-spongidepsin

asymmetric hydrogenationanti:syn 61:1.0asymmetric

hydrogenationsyn:anti 34:1.0

Asymmetric Hydrogenations to 1,2-Dimethyl Chirons.Carbon chains bearing adjacent methyl groups are observed insome natural products,29–31 but routes to these materials are stillevolving.32–37 The Burgess group’s entry into this area was in-spired by an early observation on the characteristics of Cat. Speci-fically, higher enantioselectivities were obtained from hydrogena-tions of the β-methyl esters 15 than the α-methyl systems 16 asdepicted below.

CO2MeHO β

(15a) 96% ee

CO2MeTBDPSO β

(15b) 93% ee

CO2Meα

HO

(16a) 53% ee

CO2Meα

TBDPSO

(16b) 67% ee

The observations shown above implied that substrates of thegeneric types E might be well suited for syntheses of 1,2-dimethylchiron F. It appeared that both the syn- and anti-isomers of thissystem could be obtained by varying the protection and functionalgroups as implied in eq 21.

protecting and functional groups, P and FG, varied for optimization of stereoselectivities

FGPO

(S)-Cat

(R)-Cat

50 bar H2

FGPO

FGPO

anti-F

syn-F

(21)

E

The anti-isomer of F was obtained from enoate 17, while al-lylic ether 18 was used to prepare the syn-form (eqs 22 and 23).Both the reactions were catalyst controlled, but ‘substrate vectors’(contributions to the diastereoselectivity by the substrate) were

6 (η4-1,5-CYCLOOCTADIENE)(1-[(4S)-(2-(1-ADAMANTYL)-4,5-DIHYDROOXAZOLYL)ETHYL]

significant. This methodology was subsequently used to obtain(−)-lasiol and the central fragment of (+)-kalkitoxin.38

CO2EtPO

CO2EtPO

(17) (R)-Catsyn:anti 2.1:1.0

(S)-Catsyn:anti 1.0:20

50 bar H2

0.01 Cat(22)

P = TBDPS

CH2Cl225 °C, 4 h

conv >99%

(R)-Catsyn:anti 15:1.0

(S)-Catsyn:anti 1.0:3.0

50 bar H2

0.01 Cat(23)

P = TBDPS

HO OP HO OP

(18)

CH2Cl225 °C, 4 h

conv >99%

HO

(–)-lasiol

NS

N

O

(+)-kalkitoxin

Asymmetric Hydrogenation to 1,2-HydroxymethylChirons. Asymmetric hydrogenations of chiral α-oxyalkenesgenerate chirons that are typically made via aldol reactions.Stereoselective hydrogenations of chiral allylic alcohols Gwere extensively investigated about two decades ago.39–42 Allthose reactions were substrate controlled (eq 24), hence it wasimpossible to obtain both the syn and anti aldol fragments byvarying the catalyst chirality alone.

1 atm H2

0.002 (BINAP)Ru(OAc)2R2

OH

R1

G

R2

OH

R1

[(R)-BINAP]Ru(OAc)2 1.0:23[(S)-BINAP]Ru(OAc)2 1.0:23

(24)

syn:anti

MeOH, 25 °C, 12 h

>99% conv

Metal diphosphine complexes can be used in these reactionsbecause the alkenes are relatively unhindered 1,1-disubstituted

olefins. However, the same catalysts could not be used effectivelyon the isomeric trisubstituted alkenes because they are too hin-dered; this reaction requires chiral analogs of Crabtree’s catalystslike Cat. In the event, Cat provided high levels of catalyst controlallowing both the syn- and anti-isomers to be obtained with highdiastereoselectivities (eq 25).43

(25)

OH

H

OH

I

R = H or alkyl

terminal internal

all stereoisomers possible

RalkenesH2, 25 oC

oriridium

carbene-oxazolinecatalyst

Optically pure lactic acid was transformed into substrates 19and 20 for access to generic type H chirons. The best syn-selectivity was obtained from the allylic alcohol 19 (syn:anti61:1.0; eq 26). Good anti-selectivity was derived by MOM pro-tecting the alcohol 19 to give the ether substrate 20 (syn:anti1.0:10; eq 27). Both the products can be purified via flash chro-matography to give improved diastereoisomeric purities.

(26)OEt

(19)(R)-Catsyn:anti

crude: 1.0:2.0not purified

(S)-Catsyn:anti

crude: 61:1.0purified: >99:1.0

75% isolated

50 bar H2

0.005 Cat

O

OHOEt

O

OHCH2Cl2

25 °C, 12 h>99% conv

5 bar H2

0.005 Cat(27)OEt

(20) (R)-Catsyn:anti

crude: 1.0:10purified: 1.0:31

68% isolated

(S)-Catsyn:anti

crude: 27:1.0not purified

O

OMOMOEt

O

OMOMCH2Cl2

25 °C, 12 h>99% conv

Optically pure glycitol acetonide was transformed into alkene21 to access chiron I, in a similar way to the previous reactionsusing lactic acid derivatives. The best syn-selectivity was obtainedfrom (E )-alkene 21 (syn:anti 25:1.0) with (R)-Cat. Excellent anti-selectivity was obtained from the same substrate simply by using(S)-Cat (syn:anti 1.0:26; eq 28); that is, the substrate vector inthese reactions was completely overwhelmed.

(η4-1,5-CYCLOOCTADIENE)(1-[(4S)-(2-(1-ADAMANTYL)-4,5-DIHYDROOXAZOLYL)ETHYL] 7

5 bar H2

0.005 Cat(28)OEt

(21)

(R)-Catsyn:anti

crude: 25:1.0purified: 40:1.0 84% isolated

(S)-Catsyn:anti

crude: 1.0:26purified: 1.0:53

78% isolated

O

OO

OEt

O

OO

CH2Cl225 °C, 12 h>99% conv

Conclusion. Chiral analogs of Crabtree’s catalyst Cat are al-most uniquely suitable for asymmetric hydrogenation of coordi-nating unfunctionalized, trisubstituted alkenes. Hydrogenations ofthese relatively hindered substrates typically would not be inducedat a significant rate using metal diphosphine complexes. In mostcases, Cat usually can give catalyst control for hydrogenations ofchiral alkenes. Metal diphosphine complexes hydrogenate thesesubstrates well only if there is a coordinating functional group, inwhich case substrate control is usually observed.

Syntheses of 1,3-dimethyl,24,25,44 1,3-hydroxymethyl,26,28 1,2-dimethyl,38 and 1,2-hydroxymethyl43 chirons are discussed here.Catalyst control was optimized to give high diastereoselectivi-ties by using the following strategy. First, the catalyst enantiomerthat matched with the substrate vector was determined. The sub-strate structures are then modified to find two extremes, that is,those that enhance the matching effect and those that reverse it.The following substrate variables can be used to achieve this: (i)alcohol protecting groups (changed or removed to give free hy-droxyls); (ii) alkene geometries; and (iii) functional group inter-conversion between ester and allylic alcohols (or protected allylicalcohols). This approach almost invariably enabled preparationof all diastereoisomers of targeted chirons with good diastereo-selectivities.

1. Perry, M. C.; Cui, X.; Powell, M. T.; Hou, D.-R.; Reibenspies, J. H.;Burgess, K., J. Am. Chem. Soc. 2003, 125, 113.

2. Crabtree, R. H., Acc. Chem. Res. 1979, 12, 331.

3. Crabtree, R. H.; Felkin, H.; Morris, G. E., J. Organomet. Chem. 1977,141, 205.

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Ye Zhu & Kevin BurgessTexas A&M University, College Station, TX, USA