Diastereoselective hydroalkoxycarbonylation of terpenes and vinyl-estrone

Journal of Molecular Catalysis A: Chemical 165 (2001) 15–21

Diastereoselective hydroalkoxycarbonylation of terpenes and vinyl-estrone Csilla Benedek a , László Prókai b , Szilárd Tõrös c , Bálint Heil c,∗ a

Research Group for Petrochemistry of the Hungarian Academy of Sciences, P.O. Box 158, H-8201 Veszprém, Hungary b Center for Drug Discovery, College of Pharmacy, University of Florida Health Science Center, P.O. Box 100497, Gainesville FL 32610-0497, USA c Department of Organic Chemistry, University of Veszprém, H-8201 Veszprém, Hungary Accepted 4 August 2000

Abstract Hydroalkoxycarbonylation of several monoterpenes (limonene, carvone, dihydrocarvone, pulegone) has been carried out with chiral and achiral palladium–phosphine catalysts. Despite high chemo- and regioselectivities toward the chiral linear products, diastereoselectivity is rather low and cannot be influenced significantly by the selection of the chiral ligand. This observation is in contrast with the high diastereoselectivity of the hydroalkoxycarbonylation of vinyl-estrone used as a model of a vinyl-aromatic skeleton. © 2001 Elsevier Science B.V. All rights reserved. Keywords: Monoterpenes; Steroid; Palladium; Hydroalkoxycarbonylation; Diastereoselectivity

1. Introduction The palladium-catalyzed hydroalkoxycarbonylation of unsaturated compounds which affords the corresponding esters with one more carbon atom is an elegant synthesis of molecules with potential biological activity [1–4]. Biological activity is often associated with chirality, which underscores the utmost importance of access to synthetic procedures that yield pure enantiomers or epimers. Despite the serious progress achieved in controlling the chemo- and regioselectivity [5–10], only a few reports on successful asymmetric hydroesterification are disclosed [11–17]. The best results have been reported in the transformation of arylethenes, precursors of 2-aryl∗ Corresponding author. Tel.: +36-88-422022/ext. 4166; fax: +36-88-427492. E-mail address: [email protected] (B. Heil).

propionic acids, known as non-steroidal antiinflammatory drugs [18,19]. Using a PdCl2 –CuCl2 –HCl-(S)or (R)-BNPPA ((S)-(+)- or (R)-(−)-1,10 -binapthyl-2, 20 -diyl-hydrogen phosphate, see Fig. 1) system, Alper et al. obtained the corresponding esters with 83–91% enantioselectivity (e.e.) at ambient temperature and CO pressure [16]. The best optical control (99% e.e.) has been reported by Zhou et al. for styrene with PdCl2 –CuCl2 –DDPPI (1,4:3,6-dianhydro-2,5dideoxy-2,5-bis(diphenylphosphino)-l-iditol, see Fig. 1) as catalyst [17]. However, the substrates in these reactions have been almost exclusively of aromatic structure. As major naturally occuring chiral pools, the abundance and easy availability of their pure antipodes makes terpenes attractive candidates for the construction of chiral derivatives [20]. Their oxygenated compounds in particular are of considerable value for perfumery, flavor, herbicide and pharmaceutical

1381-1169/01/$ – see front matter © 2001 Elsevier Science B.V. All rights reserved. PII: S 1 3 8 1 - 1 1 6 9 ( 0 0 ) 0 0 3 7 8 - 2

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C. Benedek et al. / Journal of Molecular Catalysis A: Chemical 165 (2001) 15–21

Fig. 1. Structure of the DDPPI and (R)-BNPPA ligands.

industries [1,3,21]. The epimers are frequently used as chiral building blocks. It has been reported that the Pd(PPh3 )2 Cl2 /SnCl2 / PPh3 catalyzed alkoxycarbonylation of limonene, isopulegol and isopulegyl acetate yields the corresponding linear esters or lactones [1]. Other monoterpenes like trans-isolimonene, carvone, dihydrocarvone and pulegone were transformed similarly with the same catalyst system, the main product being generally the linear ester [2]. Da Rocha et al. investigated the reactions of bicyclic monoterpenes such as ␤-pinene and camphene, the last being succesfully transformed into the linear ester under the above catalytic conditions [3]. Diastereoselective cyclocarbonylation of isopulegol has been performed in the presence of palladium complexes containing no chiral ligands. Diastereomeric excesses up to 60% have been related as a result of the asymmetric induction exerted by the substrate itself [27]. Similarly, our paper deals with the investigation of asymmetric hydroesterification of (+)-(R)-limonene (1), (−)-(R)-carvone (2), (+)-dihydrocarvone (3) and (−)-pulegone (4) (Fig. 2) using several effective catalysts reported. These results have been compared with the data obtained in transformation of vinyl-estrone (5, see Fig. 3) [22],

Fig. 2. Starting monoterpenes and the derived ester products.

a model of a vinyl-aromatic skeleton of obvious biological importance.

2. Experimental The terpenes used as substrates were purchased from commercial sources (Fluka, Janssen) and have been used without further purification. Solvents were dried by standard procedures and stored under argon atmosphere. PdCl2 , DIOP (2,3-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane), BNPPA

Fig. 3. Hydroalkoxycarbonylation of vinyl-estrone.

C. Benedek et al. / Journal of Molecular Catalysis A: Chemical 165 (2001) 15–21

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were Aldrich and Fluka products. Palladium complexes PdP2 Cl2 (P = PPh3 , P2 = DIOP) and Pd(PhCN)2 Cl2 were prepared according to the literature [18,19]. DDPPI was prepared as described earlier and was kindly lent by Prof. J. Bakos [23]. DBP-DIOP (2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(5H-dibenzophospholyl)butane) was a gift of Prof. M. Tanaka. In a typical hydroalkoxycarbonylation experiment, a solution of 4.5 mmol terpene, 61 mmol EtOH in 20 ml toluene was transferred under argon into a 50 ml stainless steel autoclave containing the catalyst precursor (0.045 mmol Pd-complex, 0.11 mmol SnCl2 ·2H2 O and 0.09 mmol PPh2 - if any). The autoclave was pressurized to the given CO pressure, placed into a thermostated oil bath and stirred magnetically. The reaction was followed by GLC. Column chromatography on silicagel (eluents: hexane, benzene, chloroform, dichloromethane, acetone) yielded the desired compounds. The isolated products were characterized by GC-MS and by 1 H and 13 C NMR spectroscopy. The terpene-derived epimers were separated by normal-phase HPLC using an enantioselective stationary phase. The 1 H and 13 C NMR spectra were recorded in CDCl3 on a Varian Unity (Palo Alto, CA) spectrometer at 300 and 75.5 MHz, respectively with TMS as internal standard. GLC analyses were performed on a Hewlett-Packard (Palo Alto, CA) HP 5830 gas chromatograph equipped with a Supelco (Bellefonte, PA) SPB-1 column (30 m × 1 ␮m film depth) using a flame ionisation detector and helium as carrier gas. The MS-spectra were obtained on a HP 5971A GC-MSD spectrometer. The HPLC system consisted of a ThermoQuest (formerly Spectra Physics, San Jose, CA) SP 8810 precision isocratic pump, an SP 8450 variable-wavelenght UV–VIS detector, and an SP 4290 computing integrator. Injections were made by a Rheodyne (Cotati, CA) 7125 valve fitted with a 10-microliter loop. The column used was 25 cm × 4.6 mm i.d. 5 ␮m Supelcosil LC-(R)-DNB-PG (Supelco), the eluent was hexane(99.6%)/i-PrOH(0.4%) at 1.0 ml/min flow rate.

(m, 2H, C16 H2 ); 3.63 (first diastereomer) and 3.73 (second diastereomer) (q, 1H, CHCH3 ); 4.12 (q, 2H, COOCH2 ); 6.57 (s, 1H, C4 H); 6.64 (d, 1H, C1 H); 7.10 (d, 1H, C2 H). 13 C NMR (δ, CDCl3 ): 220.85 (first diastereomer) and 220.73 (second diastereomer) (C17 O); 174.36 (COOEt); 138.10; 137.66 and 137.44; 131.74 and 131.62; 131.14; 125.99; 60.33 and 60.03 (OCH2 )50.01 and 49.98; 47.62 and 47.60; 44.64 (CHCH3 ); 43.89 and 43.54; 37.94 and 37.82; 37.65 and 37.49; 31.15 and 29.07; 28.99; 27.88; 26.10; 21.17; 18.31 (CH3 CH); 15.20 (OCH2 CH3 ); 13.74 and 13.43 (C18 H3 ). MS (m/z/relative intensity): • 354/245 (M+ ); 281/1000 (M+ -COOEt); 253/240 (M+ -CH(CH3 )COOEt); 117/350. 3- (20 -carboethoxy) -estra - 1,3, 5(10)-triene-17-one (7a): 1 H NMR (in mixture with 6a)(δ, CDCl3 ): 1.25 (m, COOCH2 CH3 -overlapping with the signal of 6a); 2.9 (m, CH2 -CH2 -COOEt-partially overlapping with the signal of C16 H2 ); 4.12 (m, COOCH2 -overlapping with the signal of 6a). MS (m/z/relative intensity): • 354/1000 (M+ ); 280/850 (M+ -COOEt); 266/300 (M+ -COOEt-CH3 ); 253/150 (M+ -CH2 CH2 COOEt); 141/300. 3-(10 -carboisopropyloxy)-estra-1,3,5(10)-triene-17one (6b): 1 H NMR (δ, CDCl3 ): 0.95 (s, 3H, C18 H3 ); 1.31 (d, 6H, COOCH(CH3 )2 ); 1.55 (d, 3H, CHCH3 ); 2.92 (m, 2H, C16 H2 ); 3.62 (first diastereomer) and 3.75 (second diastereomer) (q, 1H, CHCH3 ); 4.93 (m, 1H, COOCH); 6.57 (s, 1H, C4 H); 6.64 (d, 1H, C1 H); 7.10 (d, 1H, C2 H). MS (m/z/relative intensity): • 368/100 (M+ ); 281/1000 (M+ -COOPr-i); 253/50 (M+ -CH(CH3 )COOPr-i); 117/360. 3-(20 -carboisopropyloxy)-estra-1,3,5(10)-triene-17one (7b): MS (m/z/relative intensity): 368/1000 • (M+ ); 280/800 (M+ -COOPr-i); 253/125 (M+ -CH2 CH2 COOPr-i).

2.1. Analytical data

Our studies of chiral catalytic systems were preceeded by alkoxycarbonylation of (R)- and (S)-limonene (1), (−)-carvone (2), (+)-dihydrocarvone (3) and (−)-pulegone (4) in presence of Pd(PPh3 )2 Cl2 (Scheme 1). As shown in Table 1, both conversions

3- (10 - carboethoxy)- estra- 1, 3,5(10)-triene-17-one (6a) 1 H NMR (δ, CDCl3 ): 0.95 (s, 3H, C18 H3 ); 1.25 (t, 3H, COOCH2 CH3 ); 1.55 (d, 3H, CHCH3 ); 2.92

3. Results and discussion 3.1. Hydroalkoxycarbonylation of monoterpenes with achiral catalysts

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C. Benedek et al. / Journal of Molecular Catalysis A: Chemical 165 (2001) 15–21

Scheme 1. Hydroalkoxycarbonylation of monoterpenes and the products resulted.

and chemoselectivities were found as moderate (run 1), in accordance to previous results [1,3]. The extremely low catalytic activity in the case of pulegone is probably due to the reduced access to the double bond. Apart from carvone, the isomerization of the substrates is significant in each case (the reaction of limonene for example yielded 46% mixture of ␣- and ␥-terpinene and ␣-terpinolene). Addition of ethanol to the exocyclic double bonds forming the corresponding ethers was also detected (up to 5%). In order to examine the effect of SnCl2 , the catalytic system as well as the reaction parameters chosen by Kalck and co-workers [2] were adapted and a significant increase of both chemo- and regioselectivity and catalytic activity observed (run 2). As with camphene [3], the very low activity of Pd(PPh3 )2 Cl2 toward pulegone was enhanced by the decrease in the electron density from the central palladium atom by the SnCl3 − ligand, making olefin coordination more attractive. Upon studying the internal chiral induction in hydroalkoxycarbonylation of limonene and carvone, the ratio of the resulting epimers was determined by HPLC, 1 H and 13 C NMR techniques; however, very low values were detected. In our efforts of directing regioselectivity towards the branched ester, the effect of added LiCl, HCl [26] or CuCl2 [9] was examined, but no significant effect observed. Working under Alper’s oxidative conditions with formate esters [6] or EtOH [8], the regioselectivity could be only slightly influenced comparing to the values obtained with Pd(PPh3 )2 Cl2 .

3.2. Hydroalkoxycarbonylation of monoterpenes with chiral catalysts In these studies mainly limonene and carvone were transformed using palladium catalysts preformed or prepared in situ with known chiral ligands (DIOP, DBP-DIOP, DDPPI, BNPPA), under the reaction conditions given in Table 1, which are generally the same as those given in the literature [12–17]. The DIOP-containing catalysts [15] proved to be rather active in comparison to Pd(PPh3 )2 Cl2 (runs 3 and 4). In addition, both chemo- and regioselectivities are higher and the rate of substrate isomerization decreased significantly. As observed in hydroformylation [25], an increase of the reactivity occured as the planar character of the cyclohexenyl ring increased. Consequently, in presence of the bis-phosphine ligands investigated, chemoselectivity is generally higher in the case of carvone than that of limonene. Unfortunately, the diastereoselectivity of the reaction could not be enhanced, although use of the opposite enantiomer of DIOP caused a reversal of the diastereomeric ratio, again similarly to hydroformylation [25]. Hydroalkoxycarbonylation of carvone was also carried out under 300 bar CO in the presence of PdCl2 /DIOP/PPh3 (Pd/P = 1/2, DIOP/PdCl2 = 0.5) (run 5) after the report of Consiglio [12] on the concomitant use of a chiral phosphine and PPh3 , but no measurable effect could be observed. The palladium catalyst prepared in situ with the DIOP-derivative DBP-DIOP [13,14] shows reduced catalytic activity in transformation of terpenes even

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C. Benedek et al. / Journal of Molecular Catalysis A: Chemical 165 (2001) 15–21

working under severe reaction conditions (run 6). However, most significant diastereoselectivity (12%) could be achieved with this ligand for carvone. Similar value, but a reversal of the epimeric ratio could be obtained with the DDPPI bis-phosphine (run 7), a ligand prepared for the first time in our laboratory [23]. Although the activity of the catalyst formed is rather moderate, chemo- and regioselectivities measured are satisfactory. Known as a chiral resolving agent, (R)-BNPPA was active and efficient in enantioselective hydroalkoxycarbonylation of aryl-ethenes [16]. However, the activity of the corresponding catalyst was moderate and the diastereoselectivity again unexpectedly low (run 8) in transformation of terpenes. Other chiral phosphines like NMDPP (neomenthyldiphenylphosphine) [24], BDPP (2,4-bis(diphenylphosphino)pentane), CHIRAPHOS ((2S,3S)-2,3-bis (diphenylphosphino)butane) were found to be rather inactive for hydroalkoxycarbonylation of the terpenes investigated.

ence of some achiral and chiral palladium catalysts (Table 2). The ratio of the resulting steroidal epimers was determined by 1 H-NMR spectra integrating the pair of quartets at 3.63 and 3.73 ppm due to the CHCH3 protons. Chemoselectivity of hydroesterification was rather high in each case, but reaction rates were less favourable compared to simple aryl-ethenes. Surprisingly, in presence of the bidentate ligand DBP-DIOP (Table 2, run 3) formation of the branched ester 6 — possessing a new stereogenic centre (C-30 ) — is preferred and regioselectivity was much higher than in the case of simple vinyl-aromatics — a phenomenon also observed during hydroformylation of vinyl-estrone [22]. Although addition of SnCl2 (Table 2, run 2) results in the preferential formation of the linear isomer 7, the regioselectivity of systems containing monodentate ligands (PPh3 and BNPPA, Table 2, runs 1 and 4) is lower than in the case of styrene. Best diastereoselectivity was detected when PPh3 was applied. This value could not be reached using any of the chiral ligands tested. The high internal asymmetric induction observed in presence of PPh3 pointed to the importance of the steroidal skeleton and the aromatic ring in the substrate, providing thus the necessary rigidity of the structure. This latter is absent in terpenes, which may be responsible for the enormous difference in diastereoselectivity of the reaction discussed and is, again, in accordance with the findings in hydroformylation of the same derivatives.

3.3. Hydroalkoxycarbonylation of vinyl-estrone (55) The model compound (5) was synthesized by palladium-catalyzed cross-coupling between vinyltributyltin and estrone-triflate as described previously [22]. Due to its vinyl-aromatic element, vinyl-estrone may serve as a basis of comparison of diastereoselectivity in hydroalkoxycarbonylation with the results obtained in the transformation of terpenes. After purification by crystallization from i-PrOH, it was hydroalkoxycarbonylated (Fig. 3) in the pres-

Table 2 Hydroalkoxycarbonylation of vinyl-estrone with achiral and chiral catalystsa Run

Catalyst precursor

R temperature (◦ C)

Pressure CO (atm)

R time (h)

Convb (%)

Chemoselc,d (%)

Regioselb,d (%)

Ratio of diastereomerse

1. 2. 3. 4.

Pd(PPh3 )2 Cl2 Pd(PPh3)2 Cl2 /SnCl2 /PPh3 Pd(PhCN)2 Cl2 /DBP-DIOPf PdCl2 /CuCl2 /(R)-BNPPA

100 100 100 25

100 100 190 1

50 30 75 85

99 99 55 49

84 64 79 50

82 33 99 49

85/15 85/15 80/20 78/22

a Reaction conditions: for runs 1–2 [substrate]/[EtOH]=1/13.5; [Pd]/[Sn](if any)/[PPh3](if any)=1/2.5/2; [substrate]/[Pd]=100/1. For runs 3–4 the reaction conditions are those from the corresponding literature (see text). b Determined by gas-chromatography. c (Mol esters/all the products)100, main by-product: ether. d Refers to the branched isomer. e Determined by 1 H NMR. f i-PrOH used instead of EtOH.

C. Benedek et al. / Journal of Molecular Catalysis A: Chemical 165 (2001) 15–21

4. Conclusions High chemo- and regioselectivities towards the chiral linear product were detected in hydroalkoxycarbonylation of terpenes (limonene, carvone, dihydrocarvone, pulegone) in the presence of the various achiral and chiral catalysts applied. The diastereoselectivity of these reactions is, however, very low and cannot be influenced significantly by the chiral ligands available. In contrast, the high diastereoselectivities of reactions involving vinyl-estrone are in agreement with the results obtained during hydroformylation of the same substrate [22], and clearly demonstrate the importance of the aromatic structure of the steroid investigated. The strong influence of internal induction, i.e. the subordinate role of the chiral catalysts is a common characteristic of the reactions for both types of starting molecules. Acknowledgements The authors thank Z. Tuba and S. Mahó (Chemical Works of Gedeon Richter) for the estrone and G. Szalontai (University of Veszprém) for the NMR measurements. We are grateful to Prof. M. Tanaka (National Institute of Materials and Chemical Reasearch, Tsukuba, Ibaraki, Japan) for a generous gift of DBP-DIOP and to Prof. J. Bakos (University of Veszprém) for a sample of DDPPI. This work was partly supported by the Hungarian National Science Foundation (OTKA grant T-020185). References [1] T. Chenal, I. Cipres, J. Jenck, Ph. Kalck, Y. Peres, J. Mol. Catal. 78 (1993) 351.

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