CHIRALITY 3:355-369 (1991)
The Asymmetric Hydroformylation in the Synthesis of Pharmaceuticals CARL0 BOTTEGHI, STEFAN0 PAGANELLI, ALBERT0 SCHIONATO, AND MAURO MARCHETTI Dipartimento di Chimica, Universitd di Venezia, Calk Larga S . Marta, 2137, I30123 Venezia, Italy (CB., S.P., A S . ) and Istituto Applicazwne Tecniche Chimiche Avanzate ai Problemi Agrobiologici, CNR, Via Vienna, 2, I-07100 Sassari, Italy (M.M.)
ABSTRACT
The asymmetric hydroformylation reaction represents a potential powerful synthetic tool for the preparation of large number of different chiral products to be used as precursors of several organic compounds endowed with therapeutic activity. Essential and nonessential amino acids, 2-arylpropanoic acids, aryloxypropyl- and p-phenylpropylamines, modified p-phenylethylamines, pheniramines, and other classes of pharmaceuticals are available through enantioselective 0x0-reaction of appropriate functionalized olefins; this process is catalyzed by rhodium or platinum complexes with chiral ligands, mainly chelating phosphines, and sometimes affords very high enantiomeric excesses. Furthermore, the application of many simple optically active aldehydes arising from asymmetric hydroformylation as chiral building blocks for the synthesis of complex pharmacologically active molecules such as antibiotics, peptides, antitumor macrocycle compounds, and prostaglandins is conveniently emphasized. The possibility of a future application of this asymmetric process for the production of many synthons to obtain other valuable pharmaceuticals is widely discussed too.
KEY WORDS: enantiomerically pure compounds, chiral drugs, enantioselective hydroformylation, enantioselective catalysts, biologically active compounds INTRODUCTION
of medicinal chemistry, this situation is rapidly changing. Of the synthetic chiral pharmaceuticals introduced before 1983, only 11%were produced in the single stereoisomer form; for synthetic drugs introduced from 1983 to 1987 this amount rose to 26%.5It can be expected that by the end of this century about 80% of newly introduced synthetic drugs will be pure enantiomersS5As a matter of fact, regulatory authorities are increasingly demanding details of the nature of any isomerism potentially present in the molecule and in particular information on the effect of chirality on biological activity: the FDA as well as the EC registration procedures require information about the biological activity of both enantiomers of a racemic mixture for a p p r ~ v a lthis ; ~ fact has in turn forced industry to amend its ways.* The implications for synthetic chemists involved in the pharmaceutical industry are enormous. The potential market for synthetic chiral products in bulk form can be estimated for 1988 at a minimum of $400 million, of which 35% is covered by the side chains for p-lactam antibiotics. Taking into account current trends, it would not be surprising if this would increase to more than $2 billion by the early years of the next ~entury.~
The demand for enantiomerically pure compounds is rapidly increasing.' There is a close relationship between biological activity and absolute configuration in the sense that often only one enantiomer of a racemic compound, for instance, a drug or an agrochemical, shows the desired level of therapeutic or biological activity.'~~ Quite frequently, highly undesirable side effects or no activity at all reside in the other enantiomer.4 This aspect is, of course, of great importance in the field of pharmaceutical compounds: there are several therapeutic areas in which homochirality is a crucial factor; they include ACE inhibitors, p-blockers, antiinflammatorieslanalgesics, bronchodilatorsl spasmolytics, antihistamines, and antibiotics. Specific products sold in a configurationally unique form include Captoril, Ampicillin, and many other p-lactam antibiotics, Dextropropoxyphene, ( - )-Ephedrine, Methyldopa, and Levodopa. Nevertheless, about 25% of the drugs used today are racemic mixtures? This disappointing situation originates from the well-known fact in organic chemistry that racemic mixtures are often difficult to separate into their enantiomers or in other words technical separations are in many cases economically not attractive.6 As a result of new approaches to enantioselective Received for publication February 25, 1991; accepted May 14, 1991. synthesis and an increased awareness of the problems Address reprint requests to Car10 Botteghi at the address given above. 0 1991 Wiley-Liss,
Inc.
356
BO?TEGHI ET AL.
For the preparation of pure enantiomers on commercial scale three basic methodologies are available": (1) enantiomer separation, (2) enantioselective synthesis (catalytic or stoichiometric), and (3) transformation of naturally occurring enantiomers. The choice of the method to be employed in a particular case depends on the concomitance of different economic factors.l1 Beginning in the 1970s, enantioselective synthesis reached a level of sophistication where industrial application became feasible and competitive, in the appropriate case, with the older t e c h n ~ l o g i e s . ' ~As - ~ ~a general rule, enantioselective syntheses of commercial interest are metal-catalyzed reactions; hence a relatively small amount of (usually expensive) chiral ligand enables a large quantity of chiral products to be produced. The beneficial effects of catalytic vs. stoichiometric processes on their overall economy as well as on the environment are obvious. Many metal-catalyzed asymmetric processes disclosed in the last 20 years usually proceed in high chemical yield to give products in good-to-excellentenantiomer excess.12 They include asymmetric hydrogenation, hydrosilylation, isomerization, cyclopropanation, epoxydation, and cross-coupling reaction: these reactions have currently achieved a stage of maturity and therefore some of these, for instance, olefin hydrogenation, isomerization, carbenoid addition, and ally1 alcohol epoxydation, moved the technology to the industrial level." However, asymmetric hydroformylation, which appeared in 1972,15.16was not so intensively studied as, for instance, hydrogenation; although some outstanding results have been obtained recently, this reaction seems still to be rather far from a semiindustrial application. Some problems still aMict asymmetric hydroformylation: (1) the enantioselectivity reaches values of practical importance only in a few cases (>80%); (2) the regioselectivity toward the formation of the useful chiral aldehyde is in many cases unsatisfactory; and (3) racemization of the formed optically active aldehyde occurs frequently during the reaction itself. l7 However, this asymmetric process is expected to be adequately developed in the future. The main target, to which the chemists must direct their efforts, is setting up the preparation of catalytic systems able t o warrant both high regioselectivity and enantioselectivity for the commercially interesting chiral aldehyde. The aim of this paper is to collect and to describe the most interesting results obtained in the last 20 years in the asymmetric hydroformylation of various olefinic * CH3-
CHI
R
CHO
HCN (NH&CO,
-
substrates and in the application of the chiral aldehydes produced in the synthesis of compounds endowed with therapeutic activity. It is to be pointed out that the optically active oxoaldehydes represent immediate precursor compounds for the preparation of a pharmaceutical, as in the case of a-amino acid or a 2-arylpropanoic acid; frequently, however, they are used as chiral building blocks for building more complex molecules, as in the case of polyether antibiotic or antitumor macrocycle agents. CX-AMINOACIDS
The most important application of essential a-amino acids in medicine is transfusion,'* which is widely used to maintain the basic metabolism of nitrogen, if it is not possible to ingest proteins. Synthetic amino acids, obtained in pure crystalline form, provide transfusion products free from pyrogenic agents.lg Some essential a-amino acids such as L-arginine, L-ornitine, and L-aspartic acid are employed as drugs in some diseases.20 Other nonessential amino acids present well-known therapeutic activity: L-DOPA, for instance, is used in the treatment of Parkinson's disease; L-methyl-DOPA is an important hypotensive agent.21 Moreover, many a-amino acids are used as components in the side chain of p-lactam antibiotics, or as very useful chiral synthones for the preparation of many other pharmaceuticals of great commercial interest.22 Several aldehydes derived from the hydroformylation of simple olefinic substrates available from the petrochemical industry can be conveniently transformed into racemic a-amino acids through the classical Strecker or Bucherer r e a ~ t i 0 n . l ~ There are several well-tested methods for the separation of racemic a-amino acids into pure enantiomers, including classical and preferential crystallization techniques, crystallization-induced asymmetric transformation, resolution by entrainment, and enzymatic kinetic resolution.6 Some a-amino acids like threonine and isoleucine bear two chirality centers; in this case one of the two centers can derive from a suitable enantiomerically pure aldehyde obtained by asymmetric hydroformylation (Scheme 1). Chiral 2-methylbutanal can be prepared by enantioselective 0x0-reaction of linear butenes, while chiral 2-hydroxypropanal is available from vinylacetate. The asymmetric hydroformylation of 1-butene or (Eland (21-2-butene was carried out under various reac-
CH~-~H-CH-CO
;1
/
HN
R = QHS-
\
1. Ca(OH),
2.COZ
-
*
*
I
I
R
NH3+
CH3-CH-CH-COO
Isoleucine (from linear butenes)
R = CH3COO- 0-acetylthreonine (from vinyl acetate) Scheme 1. Chiral 0x0-aldehydesas precursors of amino acids with two chiral centers.
357
ASYMMETRIC HYDROFORMYLATION
tion conditions using different chiral catalytic com- racemization of the optical active 0x0-aldehydes, bearplexes, mainly of rhodium and platinum.16 This reac- ing a chirality center adjacent to the carbonyl group, in tion can be summarized in this way: the highest enan- the reaction solution. This drawback can be overcome, tiomeric excess reached 46.7% and was obtained in the converting the aldehyde as formed into the correspondhydroformylation of 1-butene catalyzed by [( - 1- ing configurationally stable diethyl acetal. This operDIOPIPt(SnC1,)Cl; however, the chemical yield of chi- ation is effected using triethyl ortoformate as reaction ral 2-methylbutanal (17 >20
60 82
(S) (S)
27 28
"COD, cis,cis-l,4-~yclooctadiene; acacH, acetylacetone.
H
I
358
BO?TEGHI ET AL. H,, CO, 60"C, 180 atm CHp=CH-OCOCH3
[ (-)-BPP~PtCIz/SnCIzor CH3/ [ ( - ) - B P P P~ ~ ( S ~ C I ~ ) C I
HpC-CH2-CHO
'C
I
\OCOCH3
OCOCH3
82% ee (S)
PhpP
(-)-BPPM =
&
+HZ
PPh3
I C00t.B~
Scheme 2. Asymmetric hydroformylationof vinyl acetate.
CO, Hz HC(OEt), (-)-BPPM Pt(SnC13)Cl 1
t
CH(0Et)p
,,,
Pyndinium p.toluensulfonate;acetone; A
0 CH3
(+)(R)-Alanine Scheme 4. Hydroformylationof N-vinylphthalimide.
hand, platinum catalytic systems containing the same ligands afford a low yield of chiral product, but the optical yield can achieve 70%ee.28 The a-amido- or a-imido-aldehydes, which are precursor compounds of the chiral a-amino acids, suffer obvious racemization under reaction condition^:^^ in one experiment the hydroformylation of N-vinylsuccinimmide carried out with HRh(CO)(PPh,),/( - 1DIPHOL gave a chiral aldehyde with 72.5%ee; this result, however, was no longer reproduced and only a 40%optically pure product would be isolated from the reaction solution.29 The less expensive chiral ligand (-)-DIOP was shown to be less efficient than the related ligand ( - )-DIPHOL as far as stereoselectivity is concerned: with the former ligand enantiomeric excesses up to 18%only were reached.27
N-Vinylphthalimide undergoes hydroformylation (50%conversion in 5 days) in the presence of Rh(I)/(- 1DIPHOL to yield the branched product almost exclusively, but in low ee (34.1%).Use of the [(-IDIPHOLlF't(SnC1,)Cl catalyst allowed a faster reaction with a higher ee (70%),but low aldehyde selectivity was obtained (57%)(Scheme 4).27 The hydroformylation of N-vinylphthalimide in the presence of [( - 1-BPPMI PtCl2/SnCl2gave a 52% conversion and 85%chemoselectivity, but the regioselectivity was not in favor of the useful branched aldehyde (bln = 0.5). The branched ( + )-(R)-isomer,obtained in 73%ee, could be isolated by liquid chromatography and oxidized without racemization to the corresponding acid in 72% optical purity (Scheme 4)." Also in this case the use of triethylortoformate as the
359
ASYMMETRIC HYDROFORMYLATION
solvent inhibits racemization: under the above reaction (NSAI),2-arylpropanoic acids represent a class of pharconditions 2-phthalimidopropanal diethyl acetal was maceuticals of considerable therapeutic and commerobtained after a considerably longer reaction time with cial interest.35 Owing to their particular structure they can be prepractically the same chemo- and regioselectivity found in benzene solution, but with an ee higher than 96% pared in a relatively expeditious way by hydroformylation of suitable vinyl-aromatic compounds followed (Scheme 4).28 Recently, interesting results on asymmetric hydro- by oxidation of the useful branched aldehyde formed formylation of methyl N-acetamidoacrylate, one of the (Scheme 6). There are, however, some important limitations for most popular substrates for asymmetric hydrogenation," by rhodium phosphine catalysts have been re- the above described synthetic scheme: (1) vinylported.30 This process is efficiently catalyzed by HRh- aromatic substrates are not always readily available; (CO)(PPh3I3 in the presence of a chiral chelating (2) usually the more expensive rhodium catalytic sysdiphosphine: using DIOP or the strictly related ligand tems warrant the desired chemo- and regioselectivity DIOCOL, chemoselectivities as high as 90% were ob- for the introduction of formyl group in a-position with tained and the reaction that resulted was almost re- respect to the aromatic ring. In fact, cobalt and platigiospecific toward the formation of the more branched num catalysts display a lower chemoselectivity due to aldehyde, where the formyl group is bound to a chiral the occurrence of side reactions, and promote a higher tetra-substituted carbon atom (Scheme 5). Operating formation of the commercially less interesting linear at 60°C, 100 atm (H2/C0 = 10) and substrate-to- aldehyde. rhodium molar ratio = 100, more than 90% isolated Various rhodium carbonyl complexes have been used yield of methyl (R)-2-acetamido-2-formylpropanoate as catalysts in the hydroformylation of vinyl-arowith about 50% ee could be obtained in 70 h in the matics3? the yields often reached 90% and the final presence of the previous catalytic system. Higher ees acid (or ester) obtained by oxidation of the oxo(about 60%) required a lower reaction temperature aldehyde is sufficiently pure for cornmerciali~ation.~~ Several 2-arylpropanoic acids, for instance, Ibu(30°C)and hence longer times and resulted in a slightly lower yield. Surprisingly, more titled chiral ligands profen, are still used as antiinflammatory agents as a like CHIRAPHOS,31 BPPM,PNPP,32 BINAP,33 and racemic mixture. However, it is well known that freDIPMC3* gave inferior results than DIOP. Remark- quently the desired antiinflammatory activity of such ably, the above described asymmetric process can in molecules resides predominantly in one of the enantioprinciple give rise to two valuable chiral intermedi- mers: an illustrative example is given by Naproxen, for ates: methyl 2-acetamido-3-formylpropanoate,which is which the (&antipode is 28 times more active than the a precursor of aspartic acid, and methyl 2-acetamido- (R)-antipode. Hence, the work of chemists directed to 2-formylpropanoate, which can be envisaged as a more convenient synthetic routes, alternatives to the source of a-methylamino acids. For instance, this latter classical and expensive resolution procedures, for the compound was readily converted into ( - )-(R)-a- production of optically pure 2-arylpropanoic acids with methylserine by racemization free NaBH, reduction of the correct configuration is particularly important. There are in principle two industrially viable methods the formyl group (Scheme 5 L 3 O involving hydroformylation to fulfill such a task: (1) 2-ARYLPROPANOIC ACIDS the synthesis of racemic 2-arylpropanoic acid followed Among the nonsteroidal antiinflammatory agents by enantiomer resolution; and (2) the straightforward
CHp=C
/
COOCHj
\ NHC0CH3
CO, H2 HRh(CO)(PPh,)&-)-DIOP or HRh(CO)(PPh,)~(-)-DIOCOL
COOCHj
COOCHj
1. N a B H m
2.H30+
(R) Scheme 5. Asymmetric hydroformylationof methyl 2-acetamidoacrylate.
360
BOTTEGHI ET AL. Ar-CH=CH2
CO, H, cat.
Oxld.
Ar-FH-CHO
-
Ar-CH-CCOOH I
CHI
CHI
Ar-fH-COOR CH3
Scheme 6. Arylpropanoic acids via hydroformylation of vinyl-aromatics.
preparation of the appropriate chiral aldehyde by asymmetric hydroformylation to be converted into the corresponding acid or ester. As for the former method, kinetic resolution using hydrolytic enzymes is a technology which is becoming increasingly popular for the industrial scale production of pure enantiomem6 Commercial development of lipase or esterase-catalyzed resolutions is in some cases well advanced: for example, the therapeutically active (S)-enantiomers of 2-arylpropanoic acid can be conveniently prepared by lipase or esterase-mediated hydrolysis of an appropriate ester. An attractive process has been developed for the synthesis of (S)-Ibuprofen; similarly, a promising industrial process for (S)-Naproxen is currently in progress by Gist-Brocades Laboratories. Enantioselectivities for the (S)-isomer up to 95 and 99.4%,respectively, are claimed.6 The unreacted (R)-antipode is then easily racemized in the presence of strong bases such as sodium methoxide. As for the later synthetic approach, the asymmetric
hydroformylation of vinyl-aromatics can lead to a variety of optically active 2-arylpropanoic acids. For a technical application, however, two conditions must be respected: the formation of the chiral aldehyde (the branched one) must be practically regioselective and the stereoselectivity toward the (S)-enantiomer must achieve a t least 80% ee. Unfortunately, the catalytically efficient Rh complexes ensure a sufficiently high regioselectivity, but the stereoselectivity in spite of numerous investigations remains low. The opposite is true for the platinum dichloride- tin dichloride-based catalytic systems. In Table 2 some of the most interesting results obtained in various hydroformylation experiments of styrene, taken as model compounds for vinyl-aromatic substrates, catalyzed by different chiral catalytic complexes of rhodium and platinum, are reported. Particularly interesting is the behavior of the complex [( - )-BPPM]PtCl,/SnCl, in the asymmetric hydroformylation of some vinyl-aromatic compounds (see Table 3): the optical yields, that under standard condi-
TABLE 2. Asymmetric hydroformylation of styrene in the presence of rhodium or platinum catalytic systems a
P
C6H,-CH=CH,-
+ CO + H,
-
*
C6H5-CH-CH0
I
+ C,H,-CH,-CH,-CHO
CH, 2-Phenylpropanal Chiral ligand ( -)-DIOP (- )-CHIRAPHOS ( -)-CHIRAPHOS ( -)-DIPHOL ( )-BzMePhP
Catalyst precursor"
HRh(CO)(PPh,) Rh4(C0),2 [Rh(NBD)Cl], [Rh(CO),ClI, + [Rh(1,5-HD)Cl], Pi-DIPHOLb [Rh(CO),C~l, ( + )-EPHOS [Rh(CO),Cll, [( - )-DIOP1Pt(SnCl3)C1 ( - )-BPPM PtCl,/SnCl, Pi-BPPM' PtCI,/SnCl, ( - )-DIPHO1 PtCl,/SnCl, [( - )-DIOPlPtC12/SnC12d ( - )-DIPHOL PtC1,(PPh3),/SnC1, (Pro-NOP),PtCl,/SnCl, [Bco-dbp]PtCl,/SnCl,
T
PH, (atm)
PCO (atm)
Yield
ee
("C)
bln.
(%)
(%)
Configuration
0.5 6.0 40.0 50.0 70.0 50.0 6.0 125.0 97.5 85.5 234.0 13.6 40.0 65.0 150.0
0.5 6.0 40.0 50.0 70.0 50.0 6.0 125.0 97.5 85.5 80.0 13.6 40.0 65.0 70.0
25 40 100 80 60 80 40 60 56 60 36 50 20 80 50
2.1 44.0 16.8 9.0 49.0 8.4 9.1 0.5 0.4 0.5 4.4 2.7 0.4 0.7 11.5
69 96 80
22.7 25.3 24.2 27.6 28.3 27.7 30.9 28.6 78.0 73.0 79.8 46.0 88.8 48.1 85.0
(R) (R) (R) (S) (S) (R) (R) (S) (S) (S) (S) (R) (S) (S) (S)
-
18 -
57 14 8 15 12 53 4 40 79
"NBD, norbornadiene; 1,5-HD, 1,5-hexadiene;Bz, benzyl group. 'Insoluble styrene-divinylbenzenecopolymer containing ( - )-DIPHOl moiety. insoluble styrene-divinyl-benzenecopolymer containing ~2S,4S)-N-carbonyl-4-~diphenylphosphino)methyl-p~olidine group. dStyrene reacts as tricarbonyl(q6-styrene)chromium.
Ref. 37 33 16b 39 40 41 38 16 42 42 43
44 45 46 47
361
ASYMMETRIC HYDROFORMYLATION
tions range between 70 and 80%, in triethylortoformate as the solvent jump to nearly 100%.The chiral 2-arylpropanal (or its diethyl acetal) obtained, isolated from the reaction mixture, is converted by conventional experimental procedures into the corresponding acids having high chemical and optical purity. This synthetic route was successfully applied for the preparation of (S)-Ibuprofen, (S)-Naproxen, and (S)Suprofen.28 The required starting compounds, t h e vinylaromatics, are accessible from the corresponding acylderivatives2* or from the corresponding bromides by palladium-catalyzed reaction with vinyltributylstannane. To overcome the problem connected with the unsatisfactory regioselectivity found in the hydroformylation of vinyl-aromatics catalyzed by platinum complexes, changing the structure of the chiral ligand can play a very important role: since there is little difference in the enthalpies of activation producing the two TABLE 3. Asymmetric hydroformylation of vinyl-aromaticsin the presence of (- )-BPPM/PtCI,/SnCl," Branched aldehyde Substrate
Yield
ee
bln
(%I
(%I
Configuration
0.50
17
78
(S)
0.60
24
73
-
0.53
17
75
-
0.87
21
85
-
1.40
8
58
-
0.53
22
78
(S)
0.70
37
81
(S)
0.50
24
78
(S)
Br
Me0
CHBOC
02N
Me0
/o"
0
"Experimentscarried out in benzene with SnCl,/Pt = 2.5, at 60°C and at 160-170 atm of CO/H, = 1 (substrate/catalyst = 800).
Fig. 1.
(-
)-BPPM dibenzophosphole analogue.
regioisomers, it is to be expected that small changes in structure should effect large changes in the ratios. As a matter of fact, in platinum-catalyzed hydroformylation of styrene the change from DIOP ligand to the less bulky DIPHOL, changes the bln ratio from 0.5 to 4.0;43,49 changing from BPPM to the dibenzophosphole analog (Figure 1) produces a change in the bin ratio from 0.5 to 1.5.50a* An ingenious trick to improve the branched to linear aldehyde ratio in the hydroformylation of vinylaromatics was recently devised44;it was found that the readily available tricarbonyl chromium compounds of alkenylarenes such as styrene, indene, and dihydronaphthalene react with CO and H2 in the presence of rhodium or platinum catalysts to give branch chain aldehydes in good yields under mild condition and with better regioselectivity than the parent aromatic hydrocarbons. For instance, the asymmetric hydroformylation of tricarbonyl(q6-styrene)chromium in the presence of [Rh(CO),C1121(- 1-DIOP gave (R)-2-phenylpropanal in about 90% yield and 20% ee. Using [(-)DIOP]PtCl,/SnCl, a 3:l ratio of branched to linear aldehyde was obtained with an ee of 46% for the former. The increased electrophilicity of the olefinic double bond promoted by the arene-chromium complex formation forces the metal to attack the more substituted carbon atom, the most electron-rich one, of the olefinic linkage, leading preferentially to the branched intermediate o-alkyl complex and hence to the branched aldehyde. Recently outstanding results for styrene hydroformylation have been reported using the new complex [(R,R)-Bco-dbplPt(Cod)(BF,), as the catalyst precursor (Figure 2): 95% conversion after 23 h and 75% chemoselectivity were obtained with a 9218 bin ratio, which is one of the best regioselectivities ever rep ~ r t e d . ~2-Phenylpropanal ' formed in the above reaction showed prevailing ( S ) configuration and 85% ee. Using the related ligand where the dibenzophosphole group is replaced by the bulkier diphenylphosphino * More recently an interesting paper on this topic appeared,reporting outstanding results in the enantioselective synthesis of various 2-arylpropanoic acids including Ketoprofen, Suprofen, Flurbiprofen and Indobufen. Using Pt(II)/SnCl, catalytic systems embodying the ligand reported in Fig. 1 and the CH(OC,H,),-procedure b/n ratios up to 4.0 and ees 296% were achieved.
362
BOlTEGHI ET AL.
dowed with interesting vasodilator and antiallergic properties (Scheme 7). Only a few experiments on the asymmetric hydroformylation of aryl vinyl ethers are reported in the l i t e r a t ~ r ewhile ; ~ ~ the chemical yields are acceptable, the stereoselectivity of the reaction was too low for practical purpose. Also some modified P-phenylethylamines with hypotensive activity are obtained by hydroformylation of indene or acenaphthylene in the presence of rhodium catalysts and subsequent reaction of the resulting aldehydes with amines under reductive condition^.^' Both olefins gave only one aldehyde with very high chemoselectivity (95%)under standard 0x0-conditions (Scheme 8). Recently it was found that in the presence of di-p,chlorotetracarbonyldirhodiurnltriphenylphosphine (molar ratio ca. Y4) hydroformylation of acenaphthylene (molar ratio substratelcatalyst ca. 250) occurs rapFig. 2. Bco-dpp, ~R,R~-I~bicyclo~2.2.2loctane-2,3-diyl~bis(methylene)lbis[diphenylphpsphinel; Bco-dbp, (R,R)-[~bicyclo[2.2.2loctane- idly (1 h) with almost complete conversion a t 100°C and 2,3-diyl)bis(methylene~lbis~5H-benzo[blphosphinindolel. 100 atm (CO:H, = 1). Enantioselective hydroformylation using DIOP in place of diphenylphosphine gave group (Figure 2) brought about the formation of iso- lower yield (ca. 45%) of chiral aldehyde and only insigmeric aldehydes in a 43/57 bln ratio, confirming the nificant ee.54 Better results were obtained more recrucial role of the ligand framework in controlling the cently with chiral platinum complexes: thus, using regioselectivity of the platinum-catalyzed hydroformy- [(R,R)-Boc-dbplPt(Cod)(BF,), as a catalytic precursor, acenaphthylene undergoes hydroformylation giving lation. These new outcomes are expected to open new and the expected aldehyde with about 90% chemoselectivvery promising perspectives in the synthesis of opti- ity and 48%ee.47The conversion must be kept at a low cally pure 2-arylpropanoic acids through asymmetric level (35%)in order to avoid racemization of the optically unstable aldehyde formed. Indene under the same hydroformylation. It is to be mentioned that esters of 2-arylpropanoic reaction conditions produces the corresponding aldeacids are available in a single step from vinyl- hyde with 45% ee (Scheme 8). Owing to these problems, which amict the enantioaromatics by a hydrocarboalkoxylation reaction catalyzed by palladium complexes. If a racemic mixture is selective hydroformylation of aryl vinyl ethers, indene obtained, a resolution process is needed for the prepa- and acenaphthylene, the resolution of the racemic ration of the desired ($3)-enantiomer; otherwise, an amines with enantiomerically pure acids appears to be asymmetric hydrocarboalcoxylation process is also pos- still the only viable method, if a pure enantiomer is sible using chiral ligands. However, this enantioselec- needed. tive reaction was not fully developed to date; it requires 0x0-ALDEHYDES AS BUILDING BLOCKS FOR rather drastic conditions and the optical yields did not THE SYNTHESIS OF PHARMACEUTICALS reach practical values.51 Many simple optically active aldehydes derived from asymmetric hydroformylation are very useful chiral AMINES CONTAINING ARYL GROUPS building blocks for the synthesis of complex biologiThe 0x0-aldehydes a r e valuable precursors of cally active molecules. Often these aldehydes are amines, which are produced in a single step by reduc- hardly accessible by conventional methods. The chiral 2-acetoxypropanal, used as precursor in tive amination catalyzed by Ni Raney or Pt (Scheme 7). Accordingly, some classes of pharmacologically ac- the synthesis of threonine, can be converted by careful tive amines are readily prepared by regioselective hy- hydrolysis into 2-hydroxypropanal (and hence into lacdroformylation with rhodium catalysts of appropriate tic acid)24as useful intermediate in the preparation of aromatic compounds.62 Thus, the 2-aryloxy- and 2- antibiotic^^^ and pep tide^.^^ For example, Valinomyarylpropanals derived from aryl vinylethers and 1- cine (a depsipeptide with remarkable antibiotic activarylalkenes, respectively, are used for the synthesis of ity) incorporates three building units derived from 2(aryloxypropy1)amines and p-phenylpropilamines en- hydr~xypropanal.'~
Ar-
cn=
corn, Rh catalysts
-
Ar-CCH-CHO
cH3
HNR,R,/H, Ni or Pt catalyst
Scheme 7. Amines from 0x0-aldehydes.
-
Rt Ar-CCH-N
The Asymmetric Hydroformylation in the Synthesis of Pharmaceuticals CARL0 BOTTEGHI, STEFAN0 PAGANELLI, ALBERT0 SCHIONATO, AND MAURO MARCHETTI Dipartimento di Chimica, Universitd di Venezia, Calk Larga S . Marta, 2137, I30123 Venezia, Italy (CB., S.P., A S . ) and Istituto Applicazwne Tecniche Chimiche Avanzate ai Problemi Agrobiologici, CNR, Via Vienna, 2, I-07100 Sassari, Italy (M.M.)
ABSTRACT
The asymmetric hydroformylation reaction represents a potential powerful synthetic tool for the preparation of large number of different chiral products to be used as precursors of several organic compounds endowed with therapeutic activity. Essential and nonessential amino acids, 2-arylpropanoic acids, aryloxypropyl- and p-phenylpropylamines, modified p-phenylethylamines, pheniramines, and other classes of pharmaceuticals are available through enantioselective 0x0-reaction of appropriate functionalized olefins; this process is catalyzed by rhodium or platinum complexes with chiral ligands, mainly chelating phosphines, and sometimes affords very high enantiomeric excesses. Furthermore, the application of many simple optically active aldehydes arising from asymmetric hydroformylation as chiral building blocks for the synthesis of complex pharmacologically active molecules such as antibiotics, peptides, antitumor macrocycle compounds, and prostaglandins is conveniently emphasized. The possibility of a future application of this asymmetric process for the production of many synthons to obtain other valuable pharmaceuticals is widely discussed too.
KEY WORDS: enantiomerically pure compounds, chiral drugs, enantioselective hydroformylation, enantioselective catalysts, biologically active compounds INTRODUCTION
of medicinal chemistry, this situation is rapidly changing. Of the synthetic chiral pharmaceuticals introduced before 1983, only 11%were produced in the single stereoisomer form; for synthetic drugs introduced from 1983 to 1987 this amount rose to 26%.5It can be expected that by the end of this century about 80% of newly introduced synthetic drugs will be pure enantiomersS5As a matter of fact, regulatory authorities are increasingly demanding details of the nature of any isomerism potentially present in the molecule and in particular information on the effect of chirality on biological activity: the FDA as well as the EC registration procedures require information about the biological activity of both enantiomers of a racemic mixture for a p p r ~ v a lthis ; ~ fact has in turn forced industry to amend its ways.* The implications for synthetic chemists involved in the pharmaceutical industry are enormous. The potential market for synthetic chiral products in bulk form can be estimated for 1988 at a minimum of $400 million, of which 35% is covered by the side chains for p-lactam antibiotics. Taking into account current trends, it would not be surprising if this would increase to more than $2 billion by the early years of the next ~entury.~
The demand for enantiomerically pure compounds is rapidly increasing.' There is a close relationship between biological activity and absolute configuration in the sense that often only one enantiomer of a racemic compound, for instance, a drug or an agrochemical, shows the desired level of therapeutic or biological activity.'~~ Quite frequently, highly undesirable side effects or no activity at all reside in the other enantiomer.4 This aspect is, of course, of great importance in the field of pharmaceutical compounds: there are several therapeutic areas in which homochirality is a crucial factor; they include ACE inhibitors, p-blockers, antiinflammatorieslanalgesics, bronchodilatorsl spasmolytics, antihistamines, and antibiotics. Specific products sold in a configurationally unique form include Captoril, Ampicillin, and many other p-lactam antibiotics, Dextropropoxyphene, ( - )-Ephedrine, Methyldopa, and Levodopa. Nevertheless, about 25% of the drugs used today are racemic mixtures? This disappointing situation originates from the well-known fact in organic chemistry that racemic mixtures are often difficult to separate into their enantiomers or in other words technical separations are in many cases economically not attractive.6 As a result of new approaches to enantioselective Received for publication February 25, 1991; accepted May 14, 1991. synthesis and an increased awareness of the problems Address reprint requests to Car10 Botteghi at the address given above. 0 1991 Wiley-Liss,
Inc.
356
BO?TEGHI ET AL.
For the preparation of pure enantiomers on commercial scale three basic methodologies are available": (1) enantiomer separation, (2) enantioselective synthesis (catalytic or stoichiometric), and (3) transformation of naturally occurring enantiomers. The choice of the method to be employed in a particular case depends on the concomitance of different economic factors.l1 Beginning in the 1970s, enantioselective synthesis reached a level of sophistication where industrial application became feasible and competitive, in the appropriate case, with the older t e c h n ~ l o g i e s . ' ~As - ~ ~a general rule, enantioselective syntheses of commercial interest are metal-catalyzed reactions; hence a relatively small amount of (usually expensive) chiral ligand enables a large quantity of chiral products to be produced. The beneficial effects of catalytic vs. stoichiometric processes on their overall economy as well as on the environment are obvious. Many metal-catalyzed asymmetric processes disclosed in the last 20 years usually proceed in high chemical yield to give products in good-to-excellentenantiomer excess.12 They include asymmetric hydrogenation, hydrosilylation, isomerization, cyclopropanation, epoxydation, and cross-coupling reaction: these reactions have currently achieved a stage of maturity and therefore some of these, for instance, olefin hydrogenation, isomerization, carbenoid addition, and ally1 alcohol epoxydation, moved the technology to the industrial level." However, asymmetric hydroformylation, which appeared in 1972,15.16was not so intensively studied as, for instance, hydrogenation; although some outstanding results have been obtained recently, this reaction seems still to be rather far from a semiindustrial application. Some problems still aMict asymmetric hydroformylation: (1) the enantioselectivity reaches values of practical importance only in a few cases (>80%); (2) the regioselectivity toward the formation of the useful chiral aldehyde is in many cases unsatisfactory; and (3) racemization of the formed optically active aldehyde occurs frequently during the reaction itself. l7 However, this asymmetric process is expected to be adequately developed in the future. The main target, to which the chemists must direct their efforts, is setting up the preparation of catalytic systems able t o warrant both high regioselectivity and enantioselectivity for the commercially interesting chiral aldehyde. The aim of this paper is to collect and to describe the most interesting results obtained in the last 20 years in the asymmetric hydroformylation of various olefinic * CH3-
CHI
R
CHO
HCN (NH&CO,
-
substrates and in the application of the chiral aldehydes produced in the synthesis of compounds endowed with therapeutic activity. It is to be pointed out that the optically active oxoaldehydes represent immediate precursor compounds for the preparation of a pharmaceutical, as in the case of a-amino acid or a 2-arylpropanoic acid; frequently, however, they are used as chiral building blocks for building more complex molecules, as in the case of polyether antibiotic or antitumor macrocycle agents. CX-AMINOACIDS
The most important application of essential a-amino acids in medicine is transfusion,'* which is widely used to maintain the basic metabolism of nitrogen, if it is not possible to ingest proteins. Synthetic amino acids, obtained in pure crystalline form, provide transfusion products free from pyrogenic agents.lg Some essential a-amino acids such as L-arginine, L-ornitine, and L-aspartic acid are employed as drugs in some diseases.20 Other nonessential amino acids present well-known therapeutic activity: L-DOPA, for instance, is used in the treatment of Parkinson's disease; L-methyl-DOPA is an important hypotensive agent.21 Moreover, many a-amino acids are used as components in the side chain of p-lactam antibiotics, or as very useful chiral synthones for the preparation of many other pharmaceuticals of great commercial interest.22 Several aldehydes derived from the hydroformylation of simple olefinic substrates available from the petrochemical industry can be conveniently transformed into racemic a-amino acids through the classical Strecker or Bucherer r e a ~ t i 0 n . l ~ There are several well-tested methods for the separation of racemic a-amino acids into pure enantiomers, including classical and preferential crystallization techniques, crystallization-induced asymmetric transformation, resolution by entrainment, and enzymatic kinetic resolution.6 Some a-amino acids like threonine and isoleucine bear two chirality centers; in this case one of the two centers can derive from a suitable enantiomerically pure aldehyde obtained by asymmetric hydroformylation (Scheme 1). Chiral 2-methylbutanal can be prepared by enantioselective 0x0-reaction of linear butenes, while chiral 2-hydroxypropanal is available from vinylacetate. The asymmetric hydroformylation of 1-butene or (Eland (21-2-butene was carried out under various reac-
CH~-~H-CH-CO
;1
/
HN
R = QHS-
\
1. Ca(OH),
2.COZ
-
*
*
I
I
R
NH3+
CH3-CH-CH-COO
Isoleucine (from linear butenes)
R = CH3COO- 0-acetylthreonine (from vinyl acetate) Scheme 1. Chiral 0x0-aldehydesas precursors of amino acids with two chiral centers.
357
ASYMMETRIC HYDROFORMYLATION
tion conditions using different chiral catalytic com- racemization of the optical active 0x0-aldehydes, bearplexes, mainly of rhodium and platinum.16 This reac- ing a chirality center adjacent to the carbonyl group, in tion can be summarized in this way: the highest enan- the reaction solution. This drawback can be overcome, tiomeric excess reached 46.7% and was obtained in the converting the aldehyde as formed into the correspondhydroformylation of 1-butene catalyzed by [( - 1- ing configurationally stable diethyl acetal. This operDIOPIPt(SnC1,)Cl; however, the chemical yield of chi- ation is effected using triethyl ortoformate as reaction ral 2-methylbutanal (17 >20
60 82
(S) (S)
27 28
"COD, cis,cis-l,4-~yclooctadiene; acacH, acetylacetone.
H
I
358
BO?TEGHI ET AL. H,, CO, 60"C, 180 atm CHp=CH-OCOCH3
[ (-)-BPP~PtCIz/SnCIzor CH3/ [ ( - ) - B P P P~ ~ ( S ~ C I ~ ) C I
HpC-CH2-CHO
'C
I
\OCOCH3
OCOCH3
82% ee (S)
PhpP
(-)-BPPM =
&
+HZ
PPh3
I C00t.B~
Scheme 2. Asymmetric hydroformylationof vinyl acetate.
CO, Hz HC(OEt), (-)-BPPM Pt(SnC13)Cl 1
t
CH(0Et)p
,,,
Pyndinium p.toluensulfonate;acetone; A
0 CH3
(+)(R)-Alanine Scheme 4. Hydroformylationof N-vinylphthalimide.
hand, platinum catalytic systems containing the same ligands afford a low yield of chiral product, but the optical yield can achieve 70%ee.28 The a-amido- or a-imido-aldehydes, which are precursor compounds of the chiral a-amino acids, suffer obvious racemization under reaction condition^:^^ in one experiment the hydroformylation of N-vinylsuccinimmide carried out with HRh(CO)(PPh,),/( - 1DIPHOL gave a chiral aldehyde with 72.5%ee; this result, however, was no longer reproduced and only a 40%optically pure product would be isolated from the reaction solution.29 The less expensive chiral ligand (-)-DIOP was shown to be less efficient than the related ligand ( - )-DIPHOL as far as stereoselectivity is concerned: with the former ligand enantiomeric excesses up to 18%only were reached.27
N-Vinylphthalimide undergoes hydroformylation (50%conversion in 5 days) in the presence of Rh(I)/(- 1DIPHOL to yield the branched product almost exclusively, but in low ee (34.1%).Use of the [(-IDIPHOLlF't(SnC1,)Cl catalyst allowed a faster reaction with a higher ee (70%),but low aldehyde selectivity was obtained (57%)(Scheme 4).27 The hydroformylation of N-vinylphthalimide in the presence of [( - 1-BPPMI PtCl2/SnCl2gave a 52% conversion and 85%chemoselectivity, but the regioselectivity was not in favor of the useful branched aldehyde (bln = 0.5). The branched ( + )-(R)-isomer,obtained in 73%ee, could be isolated by liquid chromatography and oxidized without racemization to the corresponding acid in 72% optical purity (Scheme 4)." Also in this case the use of triethylortoformate as the
359
ASYMMETRIC HYDROFORMYLATION
solvent inhibits racemization: under the above reaction (NSAI),2-arylpropanoic acids represent a class of pharconditions 2-phthalimidopropanal diethyl acetal was maceuticals of considerable therapeutic and commerobtained after a considerably longer reaction time with cial interest.35 Owing to their particular structure they can be prepractically the same chemo- and regioselectivity found in benzene solution, but with an ee higher than 96% pared in a relatively expeditious way by hydroformylation of suitable vinyl-aromatic compounds followed (Scheme 4).28 Recently, interesting results on asymmetric hydro- by oxidation of the useful branched aldehyde formed formylation of methyl N-acetamidoacrylate, one of the (Scheme 6). There are, however, some important limitations for most popular substrates for asymmetric hydrogenation," by rhodium phosphine catalysts have been re- the above described synthetic scheme: (1) vinylported.30 This process is efficiently catalyzed by HRh- aromatic substrates are not always readily available; (CO)(PPh3I3 in the presence of a chiral chelating (2) usually the more expensive rhodium catalytic sysdiphosphine: using DIOP or the strictly related ligand tems warrant the desired chemo- and regioselectivity DIOCOL, chemoselectivities as high as 90% were ob- for the introduction of formyl group in a-position with tained and the reaction that resulted was almost re- respect to the aromatic ring. In fact, cobalt and platigiospecific toward the formation of the more branched num catalysts display a lower chemoselectivity due to aldehyde, where the formyl group is bound to a chiral the occurrence of side reactions, and promote a higher tetra-substituted carbon atom (Scheme 5). Operating formation of the commercially less interesting linear at 60°C, 100 atm (H2/C0 = 10) and substrate-to- aldehyde. rhodium molar ratio = 100, more than 90% isolated Various rhodium carbonyl complexes have been used yield of methyl (R)-2-acetamido-2-formylpropanoate as catalysts in the hydroformylation of vinyl-arowith about 50% ee could be obtained in 70 h in the matics3? the yields often reached 90% and the final presence of the previous catalytic system. Higher ees acid (or ester) obtained by oxidation of the oxo(about 60%) required a lower reaction temperature aldehyde is sufficiently pure for cornmerciali~ation.~~ Several 2-arylpropanoic acids, for instance, Ibu(30°C)and hence longer times and resulted in a slightly lower yield. Surprisingly, more titled chiral ligands profen, are still used as antiinflammatory agents as a like CHIRAPHOS,31 BPPM,PNPP,32 BINAP,33 and racemic mixture. However, it is well known that freDIPMC3* gave inferior results than DIOP. Remark- quently the desired antiinflammatory activity of such ably, the above described asymmetric process can in molecules resides predominantly in one of the enantioprinciple give rise to two valuable chiral intermedi- mers: an illustrative example is given by Naproxen, for ates: methyl 2-acetamido-3-formylpropanoate,which is which the (&antipode is 28 times more active than the a precursor of aspartic acid, and methyl 2-acetamido- (R)-antipode. Hence, the work of chemists directed to 2-formylpropanoate, which can be envisaged as a more convenient synthetic routes, alternatives to the source of a-methylamino acids. For instance, this latter classical and expensive resolution procedures, for the compound was readily converted into ( - )-(R)-a- production of optically pure 2-arylpropanoic acids with methylserine by racemization free NaBH, reduction of the correct configuration is particularly important. There are in principle two industrially viable methods the formyl group (Scheme 5 L 3 O involving hydroformylation to fulfill such a task: (1) 2-ARYLPROPANOIC ACIDS the synthesis of racemic 2-arylpropanoic acid followed Among the nonsteroidal antiinflammatory agents by enantiomer resolution; and (2) the straightforward
CHp=C
/
COOCHj
\ NHC0CH3
CO, H2 HRh(CO)(PPh,)&-)-DIOP or HRh(CO)(PPh,)~(-)-DIOCOL
COOCHj
COOCHj
1. N a B H m
2.H30+
(R) Scheme 5. Asymmetric hydroformylationof methyl 2-acetamidoacrylate.
360
BOTTEGHI ET AL. Ar-CH=CH2
CO, H, cat.
Oxld.
Ar-FH-CHO
-
Ar-CH-CCOOH I
CHI
CHI
Ar-fH-COOR CH3
Scheme 6. Arylpropanoic acids via hydroformylation of vinyl-aromatics.
preparation of the appropriate chiral aldehyde by asymmetric hydroformylation to be converted into the corresponding acid or ester. As for the former method, kinetic resolution using hydrolytic enzymes is a technology which is becoming increasingly popular for the industrial scale production of pure enantiomem6 Commercial development of lipase or esterase-catalyzed resolutions is in some cases well advanced: for example, the therapeutically active (S)-enantiomers of 2-arylpropanoic acid can be conveniently prepared by lipase or esterase-mediated hydrolysis of an appropriate ester. An attractive process has been developed for the synthesis of (S)-Ibuprofen; similarly, a promising industrial process for (S)-Naproxen is currently in progress by Gist-Brocades Laboratories. Enantioselectivities for the (S)-isomer up to 95 and 99.4%,respectively, are claimed.6 The unreacted (R)-antipode is then easily racemized in the presence of strong bases such as sodium methoxide. As for the later synthetic approach, the asymmetric
hydroformylation of vinyl-aromatics can lead to a variety of optically active 2-arylpropanoic acids. For a technical application, however, two conditions must be respected: the formation of the chiral aldehyde (the branched one) must be practically regioselective and the stereoselectivity toward the (S)-enantiomer must achieve a t least 80% ee. Unfortunately, the catalytically efficient Rh complexes ensure a sufficiently high regioselectivity, but the stereoselectivity in spite of numerous investigations remains low. The opposite is true for the platinum dichloride- tin dichloride-based catalytic systems. In Table 2 some of the most interesting results obtained in various hydroformylation experiments of styrene, taken as model compounds for vinyl-aromatic substrates, catalyzed by different chiral catalytic complexes of rhodium and platinum, are reported. Particularly interesting is the behavior of the complex [( - )-BPPM]PtCl,/SnCl, in the asymmetric hydroformylation of some vinyl-aromatic compounds (see Table 3): the optical yields, that under standard condi-
TABLE 2. Asymmetric hydroformylation of styrene in the presence of rhodium or platinum catalytic systems a
P
C6H,-CH=CH,-
+ CO + H,
-
*
C6H5-CH-CH0
I
+ C,H,-CH,-CH,-CHO
CH, 2-Phenylpropanal Chiral ligand ( -)-DIOP (- )-CHIRAPHOS ( -)-CHIRAPHOS ( -)-DIPHOL ( )-BzMePhP
Catalyst precursor"
HRh(CO)(PPh,) Rh4(C0),2 [Rh(NBD)Cl], [Rh(CO),ClI, + [Rh(1,5-HD)Cl], Pi-DIPHOLb [Rh(CO),C~l, ( + )-EPHOS [Rh(CO),Cll, [( - )-DIOP1Pt(SnCl3)C1 ( - )-BPPM PtCl,/SnCl, Pi-BPPM' PtCI,/SnCl, ( - )-DIPHO1 PtCl,/SnCl, [( - )-DIOPlPtC12/SnC12d ( - )-DIPHOL PtC1,(PPh3),/SnC1, (Pro-NOP),PtCl,/SnCl, [Bco-dbp]PtCl,/SnCl,
T
PH, (atm)
PCO (atm)
Yield
ee
("C)
bln.
(%)
(%)
Configuration
0.5 6.0 40.0 50.0 70.0 50.0 6.0 125.0 97.5 85.5 234.0 13.6 40.0 65.0 150.0
0.5 6.0 40.0 50.0 70.0 50.0 6.0 125.0 97.5 85.5 80.0 13.6 40.0 65.0 70.0
25 40 100 80 60 80 40 60 56 60 36 50 20 80 50
2.1 44.0 16.8 9.0 49.0 8.4 9.1 0.5 0.4 0.5 4.4 2.7 0.4 0.7 11.5
69 96 80
22.7 25.3 24.2 27.6 28.3 27.7 30.9 28.6 78.0 73.0 79.8 46.0 88.8 48.1 85.0
(R) (R) (R) (S) (S) (R) (R) (S) (S) (S) (S) (R) (S) (S) (S)
-
18 -
57 14 8 15 12 53 4 40 79
"NBD, norbornadiene; 1,5-HD, 1,5-hexadiene;Bz, benzyl group. 'Insoluble styrene-divinylbenzenecopolymer containing ( - )-DIPHOl moiety. insoluble styrene-divinyl-benzenecopolymer containing ~2S,4S)-N-carbonyl-4-~diphenylphosphino)methyl-p~olidine group. dStyrene reacts as tricarbonyl(q6-styrene)chromium.
Ref. 37 33 16b 39 40 41 38 16 42 42 43
44 45 46 47
361
ASYMMETRIC HYDROFORMYLATION
tions range between 70 and 80%, in triethylortoformate as the solvent jump to nearly 100%.The chiral 2-arylpropanal (or its diethyl acetal) obtained, isolated from the reaction mixture, is converted by conventional experimental procedures into the corresponding acids having high chemical and optical purity. This synthetic route was successfully applied for the preparation of (S)-Ibuprofen, (S)-Naproxen, and (S)Suprofen.28 The required starting compounds, t h e vinylaromatics, are accessible from the corresponding acylderivatives2* or from the corresponding bromides by palladium-catalyzed reaction with vinyltributylstannane. To overcome the problem connected with the unsatisfactory regioselectivity found in the hydroformylation of vinyl-aromatics catalyzed by platinum complexes, changing the structure of the chiral ligand can play a very important role: since there is little difference in the enthalpies of activation producing the two TABLE 3. Asymmetric hydroformylation of vinyl-aromaticsin the presence of (- )-BPPM/PtCI,/SnCl," Branched aldehyde Substrate
Yield
ee
bln
(%I
(%I
Configuration
0.50
17
78
(S)
0.60
24
73
-
0.53
17
75
-
0.87
21
85
-
1.40
8
58
-
0.53
22
78
(S)
0.70
37
81
(S)
0.50
24
78
(S)
Br
Me0
CHBOC
02N
Me0
/o"
0
"Experimentscarried out in benzene with SnCl,/Pt = 2.5, at 60°C and at 160-170 atm of CO/H, = 1 (substrate/catalyst = 800).
Fig. 1.
(-
)-BPPM dibenzophosphole analogue.
regioisomers, it is to be expected that small changes in structure should effect large changes in the ratios. As a matter of fact, in platinum-catalyzed hydroformylation of styrene the change from DIOP ligand to the less bulky DIPHOL, changes the bln ratio from 0.5 to 4.0;43,49 changing from BPPM to the dibenzophosphole analog (Figure 1) produces a change in the bin ratio from 0.5 to 1.5.50a* An ingenious trick to improve the branched to linear aldehyde ratio in the hydroformylation of vinylaromatics was recently devised44;it was found that the readily available tricarbonyl chromium compounds of alkenylarenes such as styrene, indene, and dihydronaphthalene react with CO and H2 in the presence of rhodium or platinum catalysts to give branch chain aldehydes in good yields under mild condition and with better regioselectivity than the parent aromatic hydrocarbons. For instance, the asymmetric hydroformylation of tricarbonyl(q6-styrene)chromium in the presence of [Rh(CO),C1121(- 1-DIOP gave (R)-2-phenylpropanal in about 90% yield and 20% ee. Using [(-)DIOP]PtCl,/SnCl, a 3:l ratio of branched to linear aldehyde was obtained with an ee of 46% for the former. The increased electrophilicity of the olefinic double bond promoted by the arene-chromium complex formation forces the metal to attack the more substituted carbon atom, the most electron-rich one, of the olefinic linkage, leading preferentially to the branched intermediate o-alkyl complex and hence to the branched aldehyde. Recently outstanding results for styrene hydroformylation have been reported using the new complex [(R,R)-Bco-dbplPt(Cod)(BF,), as the catalyst precursor (Figure 2): 95% conversion after 23 h and 75% chemoselectivity were obtained with a 9218 bin ratio, which is one of the best regioselectivities ever rep ~ r t e d . ~2-Phenylpropanal ' formed in the above reaction showed prevailing ( S ) configuration and 85% ee. Using the related ligand where the dibenzophosphole group is replaced by the bulkier diphenylphosphino * More recently an interesting paper on this topic appeared,reporting outstanding results in the enantioselective synthesis of various 2-arylpropanoic acids including Ketoprofen, Suprofen, Flurbiprofen and Indobufen. Using Pt(II)/SnCl, catalytic systems embodying the ligand reported in Fig. 1 and the CH(OC,H,),-procedure b/n ratios up to 4.0 and ees 296% were achieved.
362
BOlTEGHI ET AL.
dowed with interesting vasodilator and antiallergic properties (Scheme 7). Only a few experiments on the asymmetric hydroformylation of aryl vinyl ethers are reported in the l i t e r a t ~ r ewhile ; ~ ~ the chemical yields are acceptable, the stereoselectivity of the reaction was too low for practical purpose. Also some modified P-phenylethylamines with hypotensive activity are obtained by hydroformylation of indene or acenaphthylene in the presence of rhodium catalysts and subsequent reaction of the resulting aldehydes with amines under reductive condition^.^' Both olefins gave only one aldehyde with very high chemoselectivity (95%)under standard 0x0-conditions (Scheme 8). Recently it was found that in the presence of di-p,chlorotetracarbonyldirhodiurnltriphenylphosphine (molar ratio ca. Y4) hydroformylation of acenaphthylene (molar ratio substratelcatalyst ca. 250) occurs rapFig. 2. Bco-dpp, ~R,R~-I~bicyclo~2.2.2loctane-2,3-diyl~bis(methylene)lbis[diphenylphpsphinel; Bco-dbp, (R,R)-[~bicyclo[2.2.2loctane- idly (1 h) with almost complete conversion a t 100°C and 2,3-diyl)bis(methylene~lbis~5H-benzo[blphosphinindolel. 100 atm (CO:H, = 1). Enantioselective hydroformylation using DIOP in place of diphenylphosphine gave group (Figure 2) brought about the formation of iso- lower yield (ca. 45%) of chiral aldehyde and only insigmeric aldehydes in a 43/57 bln ratio, confirming the nificant ee.54 Better results were obtained more recrucial role of the ligand framework in controlling the cently with chiral platinum complexes: thus, using regioselectivity of the platinum-catalyzed hydroformy- [(R,R)-Boc-dbplPt(Cod)(BF,), as a catalytic precursor, acenaphthylene undergoes hydroformylation giving lation. These new outcomes are expected to open new and the expected aldehyde with about 90% chemoselectivvery promising perspectives in the synthesis of opti- ity and 48%ee.47The conversion must be kept at a low cally pure 2-arylpropanoic acids through asymmetric level (35%)in order to avoid racemization of the optically unstable aldehyde formed. Indene under the same hydroformylation. It is to be mentioned that esters of 2-arylpropanoic reaction conditions produces the corresponding aldeacids are available in a single step from vinyl- hyde with 45% ee (Scheme 8). Owing to these problems, which amict the enantioaromatics by a hydrocarboalkoxylation reaction catalyzed by palladium complexes. If a racemic mixture is selective hydroformylation of aryl vinyl ethers, indene obtained, a resolution process is needed for the prepa- and acenaphthylene, the resolution of the racemic ration of the desired ($3)-enantiomer; otherwise, an amines with enantiomerically pure acids appears to be asymmetric hydrocarboalcoxylation process is also pos- still the only viable method, if a pure enantiomer is sible using chiral ligands. However, this enantioselec- needed. tive reaction was not fully developed to date; it requires 0x0-ALDEHYDES AS BUILDING BLOCKS FOR rather drastic conditions and the optical yields did not THE SYNTHESIS OF PHARMACEUTICALS reach practical values.51 Many simple optically active aldehydes derived from asymmetric hydroformylation are very useful chiral AMINES CONTAINING ARYL GROUPS building blocks for the synthesis of complex biologiThe 0x0-aldehydes a r e valuable precursors of cally active molecules. Often these aldehydes are amines, which are produced in a single step by reduc- hardly accessible by conventional methods. The chiral 2-acetoxypropanal, used as precursor in tive amination catalyzed by Ni Raney or Pt (Scheme 7). Accordingly, some classes of pharmacologically ac- the synthesis of threonine, can be converted by careful tive amines are readily prepared by regioselective hy- hydrolysis into 2-hydroxypropanal (and hence into lacdroformylation with rhodium catalysts of appropriate tic acid)24as useful intermediate in the preparation of aromatic compounds.62 Thus, the 2-aryloxy- and 2- antibiotic^^^ and pep tide^.^^ For example, Valinomyarylpropanals derived from aryl vinylethers and 1- cine (a depsipeptide with remarkable antibiotic activarylalkenes, respectively, are used for the synthesis of ity) incorporates three building units derived from 2(aryloxypropy1)amines and p-phenylpropilamines en- hydr~xypropanal.'~
Ar-
cn=
corn, Rh catalysts
-
Ar-CCH-CHO
cH3
HNR,R,/H, Ni or Pt catalyst
Scheme 7. Amines from 0x0-aldehydes.
-
Rt Ar-CCH-N
