Patai S., Rappoport Z. 1997 The chemistry of functional groups. The chemistry of double-bonded functional groups / 0781 842

15. Hydrogenation of compounds containing CDC, CDO and CDN bonds 791

R	R
			H
P	P
R	R			O	PPh2
	R
R				N	PPh2
P	P		H	PPh2	PPh2
R	R
(P13) DuPhos	(P14) BPE		(P15)9 2		(P16)9 3
(R = Me, Et, i-Pr)9 1	(R = Me, Et, i-Pr)9 1
			RO
	NMe2
	O	OR	O		Ph
PPh2
	PPh2
Fe				OR	Men P

RO

	RO	Ph2 P RO
PPh2
(P17)9 4		(P18)9 5
Et
..
P	P	Et
Ph

(P20)9 7

OMe

..

Ph OMe P P

Ph

O O

(P22)9 9

(P19)9 6

OMe

..

P PPh2

Ph

(P21)9 8

PPh2

PPh2

(P23) R-BICHEP10 0

FIGURE 3. (continued)

792	Martin Wills

	PPh2	Ph
O
	PPh2	Ph
(P24)	8 6 d

				N
	Ph2 PO			PPh2
	(P26)10 3
FIGURE 3. (continued)
2 R	CO H		H	2
	2
			[Rh(I)diphos]
			(Ru/BINA P)
3 R	NHCOR1		CH2 Cl2 /MeOH

SCHEME 12

H

NHPPh2

NHPPh2

H

(P25)10 2

PPh2

PPh2

(P27)8 7

2 R CO2 H

**

3 R NHCOR1

is a notable exception and tends to be used in conjunction with ruthenium. This has been driven by their great synthetic importance as precursors of homochiral amino acids and their excellent compatibility with the hydrogenation process. The reduction of ˛-N-acylaminoacrylates, and in particular Z-acylaminocinnamic acids, has become a standard reaction for assessment of new phosphine ligands. The E-acylaminocinnamic acids and their derivatives tend to be less suitable as substrates although there are some exceptions1,107. Table 1 summarizes the results (optimised e.e.s only) for this standard hydrogenation process using the ligands shown in Figure 2, many of which are in the region of 99% e.e. Quantitative comparisons of relative rates are rather more difficult to find, due mainly to the variation in experimental conditions for each optimized process.

In terms of mechanisms many detailed investigations have been carried out on the DiPAMP rhodium system, which have been reported in considerable detail elsewhere1,79c,79d,107. X-ray crystallographic structures have also been obtained to support the conclusions in this regard. It is now accepted that the substrate binds to the metal phosphine complex via both the double bond and the N-acylamino unit (Figure 4), the latter interaction being essential for control of stereochemistry in the process. Hydrogen is then added to the rhodium atom and transferred to the double bond in a cis fashion. An unexpected discovery in the early days of this work was that the major diastereomeric complex between catalyst and substrate is not the one that leads to the product. Instead it is the minor, and more reactive diastereoisomeric complex which enters the catalytic cycle. A rapid equilibrium between the two forms ensures full and rapid conversion to the product1,107,108.

15. Hydrogenation of compounds containing CDC, CDO and CDN bonds 793

TABLE 1. Asymmetric hydrogenations of ˛-acylaminoacrylic acids and esters: % e.e. using ligand cited with Rh(I) unless otherwise indicated

Substrate:			CO2 H			CO2 H			CO2 H
Catalyst			NHAc Ph			NHAc Ph			NHBz
DiPAMP (P1)	94			96
DIOP (P2)	73			81
Chiraphos (P3)	91			89			99
Prophos (P4)	90			91			93
BINAP/Ru (P5)							100
Norphos (P6)	90			96			89
BPPM (P7)	95			91			84
BPPFA (P17)	57			67			55
Pyrphos (P8)				99
Skewphos (P9)				96
P10				99
Josiphos (P11)				96		(Me ester)
P12	93			99			90
Duphos (P13)				99 (Me ester)
DPPE (P14)				99 (Me ester)
P15				57			62 (Me ester 72)
P16
P18	82		(Me ester)
P19				76
P20				93		(Me ester)
P22				70
P23				99
P24				97
P25	89			94
P26							95

	HO2 C	O
	P	N
	Rh
		H
	P
		Ph

FIGURE 4

NMR studies on the rhodium complex formed between the modified ligand P21 and methyl-Z-˛-(acylamino)cinnamate revealed that a rapid exchange process takes place between the four possible pre-hydrogenation diastereoisomeric complexes. However, a single alkyl hydride complex is formed using hydrogen at < 40 °C98. The means by which asymmetric induction is achieved depends on the exact structure of the chiral environment created around the metal by the ligand, an environment which can vary dramatically with only small and subtle variations in the structure of the ligand. DiPAMP has been studied in most detail and some conclusions have been drawn about the important interactions which are involved1. The electron-donating properties of the methoxy group on DiPAMP appear not to be essential for asymmetric induction; the ethyl substituted analogue P20 also gives very high e.e.s (Table 1)97. The presentation

794	Martin Wills
of a	chiral array of phenyl rings (Figure 5)107,109 to the metal is essential; whilst P9

is an excellent ligand, the diastereoisomer P27 fails to induce e.e.s higher than 20% because it can adopt a favoured pseudo-chair conformation which presents an achiral phenyl group array (Figure 6)87. Attempts have been made to combine the directing effects of ligands with chiral backbones with those containing chiral centres at the phosphorus centres, as in compound P22 for example86b,99. Although this process is based on sound logic, the subtle effects so often found in asymmetric hydrogenations serve to confound most investigations into this area, and significant enhancements to e.e.s are rarely achieved.

Some of the most outstanding and remarkable results have been achieved using ligands which contain biaryl chirality, and in particular the ligand BINAP110. This highly rigid and versatile diphosphine forms very large and well defined chelate rings with a metal in a complex and presents a unique steric array of phenyl groups to the reactive centre. It is also unusual in that it is generally used with ruthenium(II), possibly because it is one of the few ligands which can form well defined complexes with a metal which is normally given to forming polymerization111. BINAP Ru complexes have a remarkable substrate scope and reactivity, and will continue to feature in later sections of this report. Several reports have appeared describing new practical approaches to the synthesis of metal BINAP complexes, such is the importance of this ligand83f,112. A very detailed and extensive

Ph Ph

P

	Rh	P	P
			Rh

P

Ph Ph

Chiralarray of aromatic rings

FIGURE 5

H	Ph
	Rh
	P	P	P
	P	Ph	Rh
	Ph
H	Ph

Achiralarray of aromatic rings

FIGURE 6

15. Hydrogenation of compounds containing CDC, CDO and CDN bonds 795

series of studies have resulted in a new protocol for the practical preparation and use of diallyl ruthenium(II) complexes of a wide range of chiral diphosphines113. Many other ligands have been designed using the same principles as BINAP, most notably biaryl phosphines such as P23 which give essentially identical levels of asymmetric induction in many cases101.

The ligands P13 (DuPHOS) and P14, which have been reported recently, are representative of the minority which do not rely on aromatic rings to create a chiral environment91. Some very impressive results have been achieved using these versatile ligands, which benefit from an elegant and ingenious double-C2 symmetric design concept. These ligands have notably been applied to the synthesis of unnatural amino acids. Enantiomeric excesses of up to 100% have been achieved using substrate/catalyst ratios commonly as high as 10,000, and often as high as 50,000. Like most chiral diphosphines rhodium(I) represents the metal ion of choice. Several X-ray crystallographic structures have been published which provide information about how chirality transfer is achieved in these compounds. A recent review summarizes these results91i.

The electronic nature of ligands on the phosphine donors is often crucial. In a revealing experiment the variation of the aromatic ring in a series of ligands based on P10 was clearly shown to give optimal results with reasonably electron-rich ligands (Scheme 13)88c. Electron-poor diphosphine ligands often require high pressures of hydrogen to promote reduction at reasonable rates114. In the case of ligand P11 (R-Josiphos) the high e.e.s obtained depended critically on the incorporation of cyclohexyl groups on the benzylic phosphine. Inferior results were obtained using a diphenylphosphine group at this position89a. Diphosphinite ligands such as P10 and related aminophosphine ligands102 benefit from ease of preparation (usually, simply the reaction of Ph2PCl with the amino or alcohol precursor) although few have given asymmetric inductions equal to those of other phosphines such as BINAP103.

NHAc	NHAc
	i
Ph	Ph
CO2 H	*	CO2 H
Reagents;(i) 0.005−0.010 mol%ligand P10 derivatives, 30−40 psiH2 , THF, r.t.
	F
90% e.e.	60% e.e.		O	O
		Ph	O		OPh
			Ar2 PO
	F			OPAr2
	CF3			P10 derivatives
Ph 94% e.e.	71% e.e.

CF3

SCHEME 13

796	Martin Wills

Dramatic steric effects can also operate. For example, the substitution of the phenyl rings in DIOP P2 with m-methylphenyl groups results in a reversal of the enantioselectivity115.

Provided the basic Z-acylaminocinnamic acid structure is preserved, a very wide range of substrates may be subjected to successful asymmetric hydrogenations. Scheme 14 shows a key step in the synthesis of Biphenomycin B, in which a highly selective reduction is achieved without interference from the other chiral centre79f,h. Transformations of acylaminoacrylates of this type, i.e. within peptides, have been reported in some detail6,79g. Chiraphos was the ligand of choice for the synthesis of L-phosphinothacin, a key compo-

nent of an antibiotic tripeptide (Scheme 15)89c, whilst in the case of the reduction shown in Scheme 16, (R)-Prophos was the favoured ligand82e.

BnO		OBn		BnO		OBn
		OH	i			OH
NHAc					NHAc
TMSO2 C	BcHN	CO2 Me		TMSO2 C H	BcHN	CO2 Me
Reagents:(i) [Rh(COD)(DiPAMP)]BF4 , H2 , MeOH, 72 h, r.t.
		SCHEME 14
O				O
P		CO2 H	i	P	CO2 H
Me				Me
RO				RO	H
	NHAc				NHAc
Reagents:(i) [Rh. Chiraphos], H2					91% e.e

SCHEME 15

O

N

O

MeO2 C

O

i

60%

NHCOPh

N

MeO2 C

H O

NHCOPh

Reagents: (i) [Rh.(R)Prophos]+, CH2 Cl2 , 30˚C

SCHEME 16

15. Hydrogenation of compounds containing CDC, CDO and CDN bonds 797

The asymmetric hydrogenation of ˇ-disubstituted acrylates, which may potentially lead to the incorporation of an extra chiral centre, is a challenging objective. Some excellent results have been achieved using ligands P13 (DuPHOS) and P14 (SS-Me-BPE)91h which have furnished products with e.e.s in the region of 96.0 to 98.6% (Scheme 17).

2 R	CO2 H			2 R	CO2 H
		i
3 R			H	3 R	H
	NHCOR1				NHCOR1

Reagents:(i) [Rh(P13, R = Me)]. OTf or [Rh(P14, R = Me)]. OTf. 90 psiH2

SCHEME 17

Reagents related to ˛-acylaminoacrylates. Given the key role played by an amide as a co-ordinating group in the hydrogenations of ˛-acylaminoacrylates, it would be expected that other reagents containing this group in an appropriate position would also be suitable asymmetric hydrogenation substrates. This has proved to be the case, although it should be noted that complexes of BINAP (and closely related reagents) with ruthenium have dominated this field. The acylamino group may also be incorporated at the ˇ-position of acrylates, reductions of which thus lead to ˇ-amino acids in high e.e.116. The presence of more than one acyamino group on an alkene can, however, lead to conflicting directing effects and low asymmetric indutions117. An early and notable application was in the asymmetric reductions of tetrahydroisoquinolines (Scheme 18), a process which leads directly to precursors of morphine and related alkaloids118. In this reduction process 0.5 1 mol% of the catalyst was employed and enantiomeric excesses of >99.5% were achieved. In many cases the minor diastereisomer was not observable by chiral HPLC methods.

MeO		MeO
N	O	N	O
MeO		MeO
		i
	OMe	> 99.5 e.e	OMe
	OMe		OMe

Reagents:(i) 0.5-1 mol% [Ru(R-BINAP)(OAc)2 ], 4 atm H2 , 5:1 EtOH:CH2 Cl2 , 48 h

SCHEME 18

The reduction of lactam substrates containing proximal exo double bonds may be achieved in high e.e. as demonstrated by the reduction of 3-alkylidene-2-piperidones

(Scheme 19)119. Cyclic amino acids may be prepared by, for example, asymmetric hydrogenation of 3 to 4 in up to 79% e.e.120 and the reduction of 5 to 6 in 99% e.e.121. In the latter case a number of chiral diphosphines were screened, and the best results were obtained using BINAP as a ligand with rhodium metal. Several other diphosphines, notably DuPHOS and DIOP, also performed well. The research group which produced

798	Martin Wills

		NR	NR
		i
			H
BocN	O	BocN	O

Reagents;(i) [Ru(S-BIBAP)Cl2 ]. EtOH, 50 ˚C, 1500 psiH2 , 20 h

			SCHEME 19
				Boc
				N
			H
N	CO2 Me	N	CO2 Me	N	CONHBut
CO2 Ph		CO2 Ph		COPh
(3)		(4)		(5)
			NHCOPh
Br				Br
		(7)			(8)
			NHBoc
		N	O		N
		H			H
		(9)			(10)

Boc

N

H

N CONHBut

COPh

(6)

NHCOPh

NHBoc

O

these results, based at Merck, have reported a number of other useful and highly selective reductions, for example the conversion of 7 to 8 (97% e.e.)122 and 9 to 10 (82% e.e.)123.

Acrylic acids may be reduced in high enantioselectivity using a number of asymmetric catalysts124,125, although Ru/BINAP combinations have given some of the best results126. The reduction of tiglic acid has been studied in considerable depth, and the mechanism has been examined127,128. X-ray crystallographic structures have been obtained to support many of the proposals in this respect129. Reductions of this class of compound also have the advantage that they provide a direct access to a number of very important target molecules, for example the antiinflamatory Naproxen (Scheme 20)127. Another important reduction product achieved by an analogous route is ibuprofen 11125,130. Using an appropriate catalyst, even trisubstituted acrylic acids may be reduced in high enantiomeric excesses131.

	15. Hydrogenation of compounds containing CDC, CDO and CDN bonds	799
		H
	CO2 H	CO2 H
	i
	100%
MeO	MeO
	97% ee

Reagents:(i) [Ru(S-BINAP)(OAc)2 ], MeOH, 135 atm H2 , 12 h, s/c = 215

SCHEME 20

H

CO2 H

(11)

The asymmetric hydrogenation of itaconic acid (Scheme 21) and its derivatives132 has become adopted as something of a standard by which catalysts are compared. A selection of results is given in Table 2 (e.e.s only)133,76. Further applications of related reductions

include the synthesis of the Renin inhibitor subunit 12 by reduction of 13 in 95% e.e.132 and the protease inhibitor 14 by reduction of 15 in this case in up to 84% e.e.134. For these processes the ligands of choice were either BINAP (in conjunction with Ru) or a derivative of BPPM (P7).

CO2 H		H CO2 H
	i
CO2 H		CO2 H

Reagents:(i) Chiralcatalyst (see Table 2), H2

SCHEME 21

The reduction of unsaturated esters has, until recently, proved rather more difficult to reduce in high yield and selectivity, possibly due in part to their inferior donor properties

TABLE 2. Reductions of itaconic acid with representative Rh(I) or Ru(II)/chiral diphosphine complexes (Scheme 21)

Metal/ligand	% e.e.
Ru/BINAP P5	99
Rh/Josiphos P11	98		99
P12	47		54
BICHEP P23	>96
BPPM P7	>97

800		Martin Wills
		Ph			Ph	H
	O				O
O	N	CO2 H O			N	CO2 H
ButO	N	ButO	N
	H		H
	(12)			(13)
	Ph			Ph	H
	S		S
	CO2 H				CO2 H
	(14)			(15)
′R	CO2 Me			CO2 Me
		′R
	OR		H	OR
	(16)			(17)
				H
Ar	CO2 Me	Ar		CO2 Me
	CO2 H			CO2 H
	(18)			(19)

compared to acids and amides. Some excellent recent results have been reported however, driven mainly by developments in the use of BINAP/Ru complexes. BINAP has proved to be one of the best ligands for the reduction of 16 to 17 in up to 98% yield (DiPAMP/Rh also gave an excellent result)135 whilst the related ligand BICHEMP (P23) was employed

for the reduction of dimethylitaconate in 99% e.e.101b. In a further example a modified version of DIOP was used to mediate the reduction of 18 to 19 in e.e.s of 90 94%136. A trimeric version of the phosphine P14 has been prepared and was reported to be capable of the reduction of dimethyl itaconate in up to 94% e.e.91b. In an interesting alternative approach to reduction of the same substrate, the combination of a racemic chiraphos/Rh complex with a second chiral phosphine which acts as a ‘chiral poison’ resulted in reduction up to 49% e.e. Although lower than the level using other methods, the need for an expensive diphosphine was avoided by this approach137.

The reduction of exo-˛,ˇ-unsaturated lactones in high e.e.s has recently been reported to be achievable by the use of Ru/BINAP combinations (Scheme 22)138. Some extensive studies, reported in a detailed full paper by Noyori, have been carried out to identify which factors control the enantioselectivity of the reaction. That the carbonyl group is closely involved in directing the reaction is clearly demonstrated by the observation that