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A new enantioselective synthesis of glycidates via dynamic kinetic resolution of racemic 2-chloro-3-keto esters using chiral Ru (II) complexes
Tetrahedron Letfers. Vol. 36, No. 12, pp. 2063-2066, 1995 Elsevier Science Ltd Printed in Great Britain M!40-4039195 $9.50+0.00
0040-4039(95)00182-4
A New Enantioselective Synthesis of Glycidates Via Dynamic Kinetic Resolution of Racemic 2-Chloro-3-keto esters using Chiral Ru (II) Complexes
Jean-Pierre GenCt*, M. C. Caiio de Andrade, V. Ratovelomanana-Vidal Laboratoire de Synthbse Organique, Associe au C.N.R.S., Ecole Nationale Sup&ieure de Chimie de Paris, 11 rue P. et M. Curie, 75231 Paris Cedex 05, France.
Key Words: Asymmetric Hydrogenation, Chiral Ruthenium (11) Catalysts, Dynamic Kinetic Resolution, 2,3-epoxy esters
Absiract : 2-chloro-3-keto esters were quantitatively hydrogenated to syn and anri 2-chloro-3hydroxyester by asymmetric hydrogenation with chiral rutbcnium (II) catalysts prcparcd in-situ from (COD)Ru(2-Methylally1)2 in presence of atropisomeric ligands such as MeO-Biphep and Binap, giving enantioselectivity up to 99%. 2-chloro-3-hydroxy esters were treated with different bases to give (E)and (Z)-2,3-epoxyalkanoates in 65-90% yields with 84-97% cc.
Optically active epoxy acids or esters are an extremely important class of compounds for biologically active products synthesis. In particular, optically active (2R, 3S)-3-(4-methoxyphenyl) glycidate 2 is an efficient and practical intermediate’ for the synthesis of dilthiazem hydrochloride 1, which is a potent channel blocker used for the treatment of angina pectoris and hypertension. 2 Taxol and the semisynthetic taxotere are currently considered as the most exciting compounds in cancer chemotherapy.3 The importance of taxol and taxotere’s C-13 side chains to these drugs was noted in the very earliest biological studies on these remarkable molecules. In several efficient approaches of the taxo14b,e,f and taxotere side chains 3a,b having threo substituants, (2R, 3R) methyl-3-(phenyl) glycidate 4 was used as key intermediate.4a+c.d The trans pphenylglycidate 5 also provided an efficient route to the taxol side chain 3.5
0
?IH Ar = p-methoxyphenyl N.HCI ‘\ 1
a:R=Ph b: R=O’Bu 3
2
There is still a need for developing efficient processes for the preparation of 2,4 and 5 in their enantiomerically pure form. In view of the excellent enantiodifferentiating ability of the ruthenium catalysts developed in our laboratory 6 for the reduction of olefins and keto groups, and the powerful synthetic so-called
2063
2064
dynamic resolution of racemic 2-substituted keto esters, 7 the enantioselective reduction of 2-chloro-3-keto esters* seemed to be an obvious and facile approach to the above optically active molecules. In this paper, we wish to describe a new and efficient synthesis of optically active a-chloro-Phydroxyesters using chiral ruthenium (II) catalysts (scheme 1) and their conversion to the corresponding chiral glycidates. 0
~D~f-g~~ylalW2
0
OR’ or [L; RuBr2]
OR’
R Cl
?I
Cl 7
)
g
H2
6 a R = P h R’=C2H 6 b R= p-l&O-Ph, I+=CH,
OR’
OR’
6 c R = M e , R’=C,H,
a 9
Cl 10
Scheme 1
Table 1 Hydrogenation of 2-Chloro-3-keto esters 6 with Ru(II) complexes SubsEntry trate i
6a 6a
3 4
6a 6a
5
6b
6
6b
7
6c
8
6c
Catalyst (a) (R)-binapRuBrz(l) (COD)Ru(all)#) + (R)-MeO-biphep(l)@) (R)-MeObiphepRuBr2(1) (COD)Ru(all)z + (S)-binap (0.5$) (COD)Ru(all)2 + (R)-binap (OS)@) (COD)Ru(all)2 + (S)-binap (l.O)@ (COD)Ru(all)2 + (R)-binap (I)@) (COD)Ru(all)2 r +~ (R)-binap (0.5)ceJ
Conditions Press.Temp.Time S o l v e n t atm “C h 27 2 0 EtOH 2: 5 0 6 0 CH$&
Yield(a) d.e.@) e.e.(anti)(c) e.e.(syn)(c) IO/n\ \ .-, 100 8l(syn) 31(2R,3R) 5(2R,3S) 90 35(anti) 84(2R,3R) 94(2S,3R)
60 86
50 80
60 CH2Cl2 3 CH2Cl2
90 64
44(anti) 90(2R,3R) 84(2S,3R) 92(anti) 83(2S,3S) 2(2R,3S)
5
50
16
100
83(syn) 77(2R,3R) 15(2S,3R)
80
80
1 7 CH2Cl2
90
92(anti) 94(2S,3S) 55(2R,3S)
30
27
2 0 EtOH
100
4(anti) 93(2R,3R) 93(2S,3R)
90
80
5
100
98(anti) 99(2R,3R) 67(2S,3R)
MeOH
CH2Cl2
(a) Chemical yields were determined by IH NMR ; (b) and (c) d. e. and e.e. were determined by G. C. analysis of (L)-Lactic Acid 0-acetyl esters [DB 1701(6a,6b) et HP-Ol(6c) columns] , and compared with racemic materials prepared by reduction with NaBH4; (d) all = 2-methylallyl; (e) Ruthenium complexes catalysts were prepared in-siru from a mixture of (COD)Ru(2Methylallyl)2, auopisomeric diphospines and the a-chloroj-kcto esters upon H29; (f) The absolute configurations of a-chloro-Phydroxycsters was determined by comparison of their optical roWon after ca&dytic hydrogenation with H2-Pd/C in C2HSOH/NEI3 with lhose of authentic samples (3-hydroxyestcrs).
Our results are summarized in table 1. We first investigated the hydrogenation of racemic ethyl 2chloro-3-phenyl-3-oxopropionate 6a. stereoisomers, 7a, fia, 9a
and
In
principle reduction should provide a mixture of the four possible
1Oa. This study revealed that the stereochemical course of the reduction with
P*PRuX2, (X= 2-methylallyl or Br) was noticeably influenced by the structures of the substrates, choice of solvents and the catalyst. Hydrogenation of 6a in ethanol catalysed by (R)-binapRuBr2 (prepared in-sit~u)~~ conducted under quite mild conditions (30 atm. of hydrogen, 27 “C), proceeded with a good syn diastereoselectivity (81% de), but with a very low enantioselectivity (5 and 31% ee, entry 1). Using the catalyst system[(COD)Ru(all)2 + (R)-MeO-biphep19 or (R)-MeO-biphep RuBr2a in CH2Cl2, under 60 atm. of hydrogen pressure, at 50 ‘C, hydrogenation proceeded with poor anti diastereoselectivity (35 and 44 % de respectively), but with good enantioselectivity (up to 94%, entries 2 and 3). Interestingly, use of only 0.5%
2065
of the catalyst [(COD)Ru(all)2 + (S)-binap]g, under higher pressure and temperature (86 atm., 8OT) resulted in better anti diastereoselectivity and enantioselectivity (92% de, entry 4). Reduction of 6b also gave syn selectivity with poor enantiofacial discrimination when hydrogenation was conducted in a protic solvent and under mild conditions (5 atm., 50 ‘C, entry 5). Finally using the same catalyst as for 6a [(COD)Ru (all)2 + (S)-binap (l.O%)], asymmetric hydrogenation resulted in full conversion to 7b with 92% de and 94% ee (entry 6). Reduction of 6c having an alkyl chain using [(COD)Ru(all)2 + (R)-binap] in ethanol under moderate conditions (30 atm., 27 “C), resulted in very low anti diastereoselectivity (4% de), but high enantioselectivity (93% ee, entry 7). However, when high pressure and temperature were used (90 atm., 80“(Z), hydrogenation proceeded with very high enantio- and diastereoselectivity (entry 8), giving almost exclusively 8c with 99% of enantiomeric excess.
Table 2 Synthesis of chiral glycidates from a-Chloro-P-Hydroxyesters Enuy Substrate a-Chloro-P-Hydroxyester Conditions Base/T(‘C)nime(h) e.e.(%) H O 1 K2CO3/DMF-H20 1 oa@) Ph xr\ OEt 20”C/6h 94% Cl 2
3
8a@) 84%
7 b(“) 94%
PhmOEt a
DBUl2OV2h
0 ti COOEt Ph 0 ,’ ICOOEt
P-A; p-An
OMe
Y i e l d e.e. (%) (%) 85
91(a)
9 0
84(b)
90
95(a)
65(F)
97(a)
Ph
DBU/2O”C/2h
Cl 4
Epoxides
0 -_ 4 COOMe 0
&@) 99%
NaOEt/O”C/3Omin mOEt 61 were determined by chiral HF’LC on Chiracel OD Daicel column 25 x 0.46;
.’
,ICOOEt
a) e.e. 10 pm; b) e.e were dctcrmined by GC on a XE60-polysiloxane-S-valine-S-a-phenylethylamide Chmmpack capillary column chromatography (SOm); c) The chlomhydroxyesters ga and 10a (entry 2, Table 1) were separated by MPLC column chromatography, eluent: n-hexane/AcOEt (95/5); d) The diastereoisomers 7b and 9b (entry 6, Table 1) were separated by Flash column chromatography, eluent: dichloromethane/AcOEt (95/5); c) From entry 8, Table 1; f) The optically active epoxy cstcrs wcrc obtained from crude chlorohydroxyesters.
When syn 2S,3R chlorohydroxyester 1Oa
was
treated with K2CO3 in a DMF-water mixture?b, 2R,3R
epoxide was formed in 85% yield without detection of 2S,3R phenylglycidate (entry 1). However by treatment of 8a with DBU in CH2C12, optically active trans 2S,3R phenylglycidate was obtained with 84% ee, in 90% yield (entry 2). Interestingly, upon the same conditions, 7b led to 2R,3S epoxy ester with 95% ee in 90% yield (entry 3). When the crude chlorohydroxyester 8c was treated with NaOEt in EtOH, the optically pure uans 2S,3R methylglycidate was obtained with 97% ee in moderate yield of 65% (entry 4). The efficiency of this technology was shown in the synthesis of both enantiomers of trans methylglycidate from the common racemic cr-chore-p-keto ester 11 using the catalyst system [(COD)Ru(all)2 + (S) or (R) atropisomeric ligands (0,5%)] (scheme 2). The reduction of 11 conducted with (S)-MeO-Biphep as chiral ligand at 90 atm., 80°C for 4 h, and then treated with base (DBU), afforded the 2R,3S methylglycidate 12 with 96% ee, in 90% overall yield. Inversely, use of (R)-MeO-biphep, under the above reduction and cyclization conditions, produced the 2S,3R enantiomer 13 with the same ee and overall yield.
2066
w
I-(S)-MeO-biphep
+
C0DR~(all)~
,, o
0
0
OIL%?
Cl
(+) 11
2- DBU, CH,Cl,, 20°C Scheme 2
a) ee were determined by chiral HPLC on Chiralcel OD Daicel column 25 x 0.46 cm, 10 pm; eluent: n-hexane/isopropanol(80/20).
In summary, we have established the optimal conditions for the kinetic dynamic resolutions of racemic 2-chloro-3-keto esters to produce both trans enantiomers of glycidates with very high enantioselectivity (up to 97% ee) using chiral Ru (II) complexes prepared in-situ from [(COD)Ru(2-methylally1)2]*o. This technic offers news opportunities for the preparation of biologically active products and these studies are currently under investigation. Acknowledgements : We thank CNPq (Brazil) for a grant to M. C. Cailo de Andrade. We also thank Dr M. Larchev@te, Dr Y. Petit and 0. Cabon for helpful discussions. We are also very grateful to Y. Pouet for technical assistance (HPLC analysis). We thank Dr. E. Broger and Dr. R. Schmid (Hoffman La Roche) for samples of (R)-(+)-MeO-biphep = (R)-(+)-6,6’-Dimethoxy-2,2’bis(diphenylphosphino)-l,l’-biphenyl. and (S)-(-)-MeO-biphcp. We thank Dr. Cl. Rossey (Synthelabo) for providing us analytical data of the (2R,3S)-3-(4-metboxyphenyl) glycidate. References and notes
1.
2. 3. 4.
5. 6.
7.
8. 9.
10
a) Rossey. G.; Zard, L.; Wick, A. E. E.P. 049712; b) Rossey, G.; Zard, L.; Wick, A. E. chiral 92 Proceedings Manchester U.K. 1992.51; c) Kanerva, L.T.; Sundholm, 0. J. Chem. Sot. Perkin Trans 1. 1993,13, 1385-1389; d) Inoue, H.; Matsuki, K.; Oh-lshi, T. Chem. Pharm. Bull. 1993.41. 1521-1523; e) Marsuki, K.; Sobukawa, M.: Kawai, A.; Inoue, H.; Takeda, M. Chem. Pharm. Bull. 1993,41, 643-648. a) Nagao, T.; Sate, M.; Nakajima, H. Chem. Pharm. Bull. 1973, 21,92-97. a) Guenard, D.; Gueritte-Vogelein, F.; Potier, P. Act. Chem. Res. 1993.26, 160-167; b) Sclichenmyer, W.J.; Hortobagyi, G.N.; Anhxmcer. Drugs. I991,2, 519; c) Barman, S. Chem. Eng. News. 1991,69(35), 11-18; d) For taxotere: Colin, M.; Guenard, D. : Gueritte-Voegelin, F. ; Potier, P. ; Eur. Put. Appli. E.P. 1988.253-738. a) Deng, L.; Jacobsen, E. N. J. Org. Chem. 1992,57. 43204323; b) Dcnis, J.-N.; Correa, A.; Greene, A.E. J. Org. Chem. 1991.56, 6939-6942; c) Denis J.-N.; Corrca, A.: Greene, A.E. J. Org. Chem. 1990.57, 1957-1959; d) Denis, J.-N.; Greene, A.E.; Serra, A.A.; Luche, M.-J. J. Org. Gem. 1986,51,46-50; e) Review : total and semi synthetic approach to Taxol, Tetrahedron symposia-in-print, Telrahedron. 1992.48, 6953-6964; f) For recent the first total Synthesis of taxol, Holton, R.A.; Somaza, C.; Kim, H.-B.; Liang, F.; Biediger, R.J.; Boatman, P.D.; Shindo, M.; Smith, CC.; Kim, S.; Nadizadeh, H.; Suzuki, Y.; Tao, C.; Vu, P.; Tang, S.; Zhang, P.; Murthi, K.K.; Gentile, L.N.; Liu, J.H.; J. Am. Chem. Sot. 1994,116, 1597-1598 and 1599-1600. a) Bunnage, M.E.; Davies, S.G.; Goodwin, C.J. J. Chem. Sot. Perkin Trans I. 1993, 13, 1375-1376; b) Gou. D.M.: Liu. Y.C.: Chen, C.S. J. Org. Chem. 1993.58, 1278-1289. a) Gen&t, J.-P.; Mallart, S.; Pine], C. ; Jug& S. Tewahedron : Asymmetry. 1991.2, 43-46; b) Get&t J.-P.; Pin& C.; Mallart, S.; Caihlol, N.; Laffitte J.A. Tetrahedron Lert. 1992,33(37), 5343-5346; c) Genet, J.-P.; Pinel, C.; Ratovelomanana-Vidal, V.: Mallart, S; Pfistcr, X.; Cane de Andrade, M.C.: Laffitte, J.A. Tefrahedron : Asymmetry. 1994.5, 665-674: d) GenC, J.-P.; Pinel. C.: Ratovelomanana-Vidal. V.; Mallart, S.; Pfister, X.; Bischoff, L.; Cairo de Andrade, MC.; Dames, S.; Galopin, C.; Lalfitte, J.A. Tetrahedron : Asymmetry. 1994.5, 675-690. a) GenCt, J.-P.: Mallan, S.; Jug& S., French Patent no 8911159 (August 1989); b) Gent%, J.-P.; Pinel, C.; Mallart. S.; Jug& S.; Thorimbert, S.; Laffitte, J.A. Tetrahedron : Asymmerry 1991.2, 555-567; c) Gem%, J.-P.; Ptister, X.; Ratovelomanana-Vidal, V.; Pinel, C.; Laffitte, J.A. Tefrahedron Left. 1994.35.4559-4562; d) For leading references in this area see: Noyori, R.; Ike&, T.; Okhuma, T.; Widhalm, M.; Kitamura, M.; Takaya, H.; Akutagawa, S.: Sayo. N.; Saito, T.; Takemoti. T.: Kumobayashi, H. J. Am. Chem. Sot. 1989,111, 9134-9135 and Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Sot. 1993,115, 144-152. a) For microbial asymmetric reduction of a-chloro$-keto esters see : Akita. H.; Matsukura, H.; Oishi, T.; Tetrahedron Leu. 1986,44,5397-5400; b) Cabon, 0.; Larcheveque, M.; Buisson, D.; Azerad, R. Terrahedron ,Qtr. 1992.33, 7337-7340; c) Akita, H.; Todoroki, R.; Endo, H.; Ikari, Y.; Oishi, T. Synthesis. 1993.5, 513-516. General procedure of hydrogenation: 2-chloro-3-keto esters (1 mmol) dissolved in 2 ml of anhydrous solvent were. degassed by a 3 times cycle of vacuum/argon at R.T.. This solution was transfcrcd into a 10 ml Schlenck tube filled with argon atmosphere containing (COD)Ru(2-methylally1)2 (1 equiv.) and the chiral diphosphine (1.3 cquiv.). The reaction mixture was immediately placed into an autoclave which was purged 3 times with hydrogen and pmssuriscd. Commercially available from Acres Organics.
(Received in France 8 December 1994; accepted 25 January 1995)
0040-4039(95)00182-4
A New Enantioselective Synthesis of Glycidates Via Dynamic Kinetic Resolution of Racemic 2-Chloro-3-keto esters using Chiral Ru (II) Complexes
Jean-Pierre GenCt*, M. C. Caiio de Andrade, V. Ratovelomanana-Vidal Laboratoire de Synthbse Organique, Associe au C.N.R.S., Ecole Nationale Sup&ieure de Chimie de Paris, 11 rue P. et M. Curie, 75231 Paris Cedex 05, France.
Key Words: Asymmetric Hydrogenation, Chiral Ruthenium (11) Catalysts, Dynamic Kinetic Resolution, 2,3-epoxy esters
Absiract : 2-chloro-3-keto esters were quantitatively hydrogenated to syn and anri 2-chloro-3hydroxyester by asymmetric hydrogenation with chiral rutbcnium (II) catalysts prcparcd in-situ from (COD)Ru(2-Methylally1)2 in presence of atropisomeric ligands such as MeO-Biphep and Binap, giving enantioselectivity up to 99%. 2-chloro-3-hydroxy esters were treated with different bases to give (E)and (Z)-2,3-epoxyalkanoates in 65-90% yields with 84-97% cc.
Optically active epoxy acids or esters are an extremely important class of compounds for biologically active products synthesis. In particular, optically active (2R, 3S)-3-(4-methoxyphenyl) glycidate 2 is an efficient and practical intermediate’ for the synthesis of dilthiazem hydrochloride 1, which is a potent channel blocker used for the treatment of angina pectoris and hypertension. 2 Taxol and the semisynthetic taxotere are currently considered as the most exciting compounds in cancer chemotherapy.3 The importance of taxol and taxotere’s C-13 side chains to these drugs was noted in the very earliest biological studies on these remarkable molecules. In several efficient approaches of the taxo14b,e,f and taxotere side chains 3a,b having threo substituants, (2R, 3R) methyl-3-(phenyl) glycidate 4 was used as key intermediate.4a+c.d The trans pphenylglycidate 5 also provided an efficient route to the taxol side chain 3.5
0
?IH Ar = p-methoxyphenyl N.HCI ‘\ 1
a:R=Ph b: R=O’Bu 3
2
There is still a need for developing efficient processes for the preparation of 2,4 and 5 in their enantiomerically pure form. In view of the excellent enantiodifferentiating ability of the ruthenium catalysts developed in our laboratory 6 for the reduction of olefins and keto groups, and the powerful synthetic so-called
2063
2064
dynamic resolution of racemic 2-substituted keto esters, 7 the enantioselective reduction of 2-chloro-3-keto esters* seemed to be an obvious and facile approach to the above optically active molecules. In this paper, we wish to describe a new and efficient synthesis of optically active a-chloro-Phydroxyesters using chiral ruthenium (II) catalysts (scheme 1) and their conversion to the corresponding chiral glycidates. 0
~D~f-g~~ylalW2
0
OR’ or [L; RuBr2]
OR’
R Cl
?I
Cl 7
)
g
H2
6 a R = P h R’=C2H 6 b R= p-l&O-Ph, I+=CH,
OR’
OR’
6 c R = M e , R’=C,H,
a 9
Cl 10
Scheme 1
Table 1 Hydrogenation of 2-Chloro-3-keto esters 6 with Ru(II) complexes SubsEntry trate i
6a 6a
3 4
6a 6a
5
6b
6
6b
7
6c
8
6c
Catalyst (a) (R)-binapRuBrz(l) (COD)Ru(all)#) + (R)-MeO-biphep(l)@) (R)-MeObiphepRuBr2(1) (COD)Ru(all)z + (S)-binap (0.5$) (COD)Ru(all)2 + (R)-binap (OS)@) (COD)Ru(all)2 + (S)-binap (l.O)@ (COD)Ru(all)2 + (R)-binap (I)@) (COD)Ru(all)2 r +~ (R)-binap (0.5)ceJ
Conditions Press.Temp.Time S o l v e n t atm “C h 27 2 0 EtOH 2: 5 0 6 0 CH$&
Yield(a) d.e.@) e.e.(anti)(c) e.e.(syn)(c) IO/n\ \ .-, 100 8l(syn) 31(2R,3R) 5(2R,3S) 90 35(anti) 84(2R,3R) 94(2S,3R)
60 86
50 80
60 CH2Cl2 3 CH2Cl2
90 64
44(anti) 90(2R,3R) 84(2S,3R) 92(anti) 83(2S,3S) 2(2R,3S)
5
50
16
100
83(syn) 77(2R,3R) 15(2S,3R)
80
80
1 7 CH2Cl2
90
92(anti) 94(2S,3S) 55(2R,3S)
30
27
2 0 EtOH
100
4(anti) 93(2R,3R) 93(2S,3R)
90
80
5
100
98(anti) 99(2R,3R) 67(2S,3R)
MeOH
CH2Cl2
(a) Chemical yields were determined by IH NMR ; (b) and (c) d. e. and e.e. were determined by G. C. analysis of (L)-Lactic Acid 0-acetyl esters [DB 1701(6a,6b) et HP-Ol(6c) columns] , and compared with racemic materials prepared by reduction with NaBH4; (d) all = 2-methylallyl; (e) Ruthenium complexes catalysts were prepared in-siru from a mixture of (COD)Ru(2Methylallyl)2, auopisomeric diphospines and the a-chloroj-kcto esters upon H29; (f) The absolute configurations of a-chloro-Phydroxycsters was determined by comparison of their optical roWon after ca&dytic hydrogenation with H2-Pd/C in C2HSOH/NEI3 with lhose of authentic samples (3-hydroxyestcrs).
Our results are summarized in table 1. We first investigated the hydrogenation of racemic ethyl 2chloro-3-phenyl-3-oxopropionate 6a. stereoisomers, 7a, fia, 9a
and
In
principle reduction should provide a mixture of the four possible
1Oa. This study revealed that the stereochemical course of the reduction with
P*PRuX2, (X= 2-methylallyl or Br) was noticeably influenced by the structures of the substrates, choice of solvents and the catalyst. Hydrogenation of 6a in ethanol catalysed by (R)-binapRuBr2 (prepared in-sit~u)~~ conducted under quite mild conditions (30 atm. of hydrogen, 27 “C), proceeded with a good syn diastereoselectivity (81% de), but with a very low enantioselectivity (5 and 31% ee, entry 1). Using the catalyst system[(COD)Ru(all)2 + (R)-MeO-biphep19 or (R)-MeO-biphep RuBr2a in CH2Cl2, under 60 atm. of hydrogen pressure, at 50 ‘C, hydrogenation proceeded with poor anti diastereoselectivity (35 and 44 % de respectively), but with good enantioselectivity (up to 94%, entries 2 and 3). Interestingly, use of only 0.5%
2065
of the catalyst [(COD)Ru(all)2 + (S)-binap]g, under higher pressure and temperature (86 atm., 8OT) resulted in better anti diastereoselectivity and enantioselectivity (92% de, entry 4). Reduction of 6b also gave syn selectivity with poor enantiofacial discrimination when hydrogenation was conducted in a protic solvent and under mild conditions (5 atm., 50 ‘C, entry 5). Finally using the same catalyst as for 6a [(COD)Ru (all)2 + (S)-binap (l.O%)], asymmetric hydrogenation resulted in full conversion to 7b with 92% de and 94% ee (entry 6). Reduction of 6c having an alkyl chain using [(COD)Ru(all)2 + (R)-binap] in ethanol under moderate conditions (30 atm., 27 “C), resulted in very low anti diastereoselectivity (4% de), but high enantioselectivity (93% ee, entry 7). However, when high pressure and temperature were used (90 atm., 80“(Z), hydrogenation proceeded with very high enantio- and diastereoselectivity (entry 8), giving almost exclusively 8c with 99% of enantiomeric excess.
Table 2 Synthesis of chiral glycidates from a-Chloro-P-Hydroxyesters Enuy Substrate a-Chloro-P-Hydroxyester Conditions Base/T(‘C)nime(h) e.e.(%) H O 1 K2CO3/DMF-H20 1 oa@) Ph xr\ OEt 20”C/6h 94% Cl 2
3
8a@) 84%
7 b(“) 94%
PhmOEt a
DBUl2OV2h
0 ti COOEt Ph 0 ,’ ICOOEt
P-A; p-An
OMe
Y i e l d e.e. (%) (%) 85
91(a)
9 0
84(b)
90
95(a)
65(F)
97(a)
Ph
DBU/2O”C/2h
Cl 4
Epoxides
0 -_ 4 COOMe 0
&@) 99%
NaOEt/O”C/3Omin mOEt 61 were determined by chiral HF’LC on Chiracel OD Daicel column 25 x 0.46;
.’
,ICOOEt
a) e.e. 10 pm; b) e.e were dctcrmined by GC on a XE60-polysiloxane-S-valine-S-a-phenylethylamide Chmmpack capillary column chromatography (SOm); c) The chlomhydroxyesters ga and 10a (entry 2, Table 1) were separated by MPLC column chromatography, eluent: n-hexane/AcOEt (95/5); d) The diastereoisomers 7b and 9b (entry 6, Table 1) were separated by Flash column chromatography, eluent: dichloromethane/AcOEt (95/5); c) From entry 8, Table 1; f) The optically active epoxy cstcrs wcrc obtained from crude chlorohydroxyesters.
When syn 2S,3R chlorohydroxyester 1Oa
was
treated with K2CO3 in a DMF-water mixture?b, 2R,3R
epoxide was formed in 85% yield without detection of 2S,3R phenylglycidate (entry 1). However by treatment of 8a with DBU in CH2C12, optically active trans 2S,3R phenylglycidate was obtained with 84% ee, in 90% yield (entry 2). Interestingly, upon the same conditions, 7b led to 2R,3S epoxy ester with 95% ee in 90% yield (entry 3). When the crude chlorohydroxyester 8c was treated with NaOEt in EtOH, the optically pure uans 2S,3R methylglycidate was obtained with 97% ee in moderate yield of 65% (entry 4). The efficiency of this technology was shown in the synthesis of both enantiomers of trans methylglycidate from the common racemic cr-chore-p-keto ester 11 using the catalyst system [(COD)Ru(all)2 + (S) or (R) atropisomeric ligands (0,5%)] (scheme 2). The reduction of 11 conducted with (S)-MeO-Biphep as chiral ligand at 90 atm., 80°C for 4 h, and then treated with base (DBU), afforded the 2R,3S methylglycidate 12 with 96% ee, in 90% overall yield. Inversely, use of (R)-MeO-biphep, under the above reduction and cyclization conditions, produced the 2S,3R enantiomer 13 with the same ee and overall yield.
2066
w
I-(S)-MeO-biphep
+
C0DR~(all)~
,, o
0
0
OIL%?
Cl
(+) 11
2- DBU, CH,Cl,, 20°C Scheme 2
a) ee were determined by chiral HPLC on Chiralcel OD Daicel column 25 x 0.46 cm, 10 pm; eluent: n-hexane/isopropanol(80/20).
In summary, we have established the optimal conditions for the kinetic dynamic resolutions of racemic 2-chloro-3-keto esters to produce both trans enantiomers of glycidates with very high enantioselectivity (up to 97% ee) using chiral Ru (II) complexes prepared in-situ from [(COD)Ru(2-methylally1)2]*o. This technic offers news opportunities for the preparation of biologically active products and these studies are currently under investigation. Acknowledgements : We thank CNPq (Brazil) for a grant to M. C. Cailo de Andrade. We also thank Dr M. Larchev@te, Dr Y. Petit and 0. Cabon for helpful discussions. We are also very grateful to Y. Pouet for technical assistance (HPLC analysis). We thank Dr. E. Broger and Dr. R. Schmid (Hoffman La Roche) for samples of (R)-(+)-MeO-biphep = (R)-(+)-6,6’-Dimethoxy-2,2’bis(diphenylphosphino)-l,l’-biphenyl. and (S)-(-)-MeO-biphcp. We thank Dr. Cl. Rossey (Synthelabo) for providing us analytical data of the (2R,3S)-3-(4-metboxyphenyl) glycidate. References and notes
1.
2. 3. 4.
5. 6.
7.
8. 9.
10
a) Rossey. G.; Zard, L.; Wick, A. E. E.P. 049712; b) Rossey, G.; Zard, L.; Wick, A. E. chiral 92 Proceedings Manchester U.K. 1992.51; c) Kanerva, L.T.; Sundholm, 0. J. Chem. Sot. Perkin Trans 1. 1993,13, 1385-1389; d) Inoue, H.; Matsuki, K.; Oh-lshi, T. Chem. Pharm. Bull. 1993.41. 1521-1523; e) Marsuki, K.; Sobukawa, M.: Kawai, A.; Inoue, H.; Takeda, M. Chem. Pharm. Bull. 1993,41, 643-648. a) Nagao, T.; Sate, M.; Nakajima, H. Chem. Pharm. Bull. 1973, 21,92-97. a) Guenard, D.; Gueritte-Vogelein, F.; Potier, P. Act. Chem. Res. 1993.26, 160-167; b) Sclichenmyer, W.J.; Hortobagyi, G.N.; Anhxmcer. Drugs. I991,2, 519; c) Barman, S. Chem. Eng. News. 1991,69(35), 11-18; d) For taxotere: Colin, M.; Guenard, D. : Gueritte-Voegelin, F. ; Potier, P. ; Eur. Put. Appli. E.P. 1988.253-738. a) Deng, L.; Jacobsen, E. N. J. Org. Chem. 1992,57. 43204323; b) Dcnis, J.-N.; Correa, A.; Greene, A.E. J. Org. Chem. 1991.56, 6939-6942; c) Denis J.-N.; Corrca, A.: Greene, A.E. J. Org. Chem. 1990.57, 1957-1959; d) Denis, J.-N.; Greene, A.E.; Serra, A.A.; Luche, M.-J. J. Org. Gem. 1986,51,46-50; e) Review : total and semi synthetic approach to Taxol, Tetrahedron symposia-in-print, Telrahedron. 1992.48, 6953-6964; f) For recent the first total Synthesis of taxol, Holton, R.A.; Somaza, C.; Kim, H.-B.; Liang, F.; Biediger, R.J.; Boatman, P.D.; Shindo, M.; Smith, CC.; Kim, S.; Nadizadeh, H.; Suzuki, Y.; Tao, C.; Vu, P.; Tang, S.; Zhang, P.; Murthi, K.K.; Gentile, L.N.; Liu, J.H.; J. Am. Chem. Sot. 1994,116, 1597-1598 and 1599-1600. a) Bunnage, M.E.; Davies, S.G.; Goodwin, C.J. J. Chem. Sot. Perkin Trans I. 1993, 13, 1375-1376; b) Gou. D.M.: Liu. Y.C.: Chen, C.S. J. Org. Chem. 1993.58, 1278-1289. a) Gen&t, J.-P.; Mallart, S.; Pine], C. ; Jug& S. Tewahedron : Asymmetry. 1991.2, 43-46; b) Get&t J.-P.; Pin& C.; Mallart, S.; Caihlol, N.; Laffitte J.A. Tetrahedron Lert. 1992,33(37), 5343-5346; c) Genet, J.-P.; Pinel, C.; Ratovelomanana-Vidal, V.: Mallart, S; Pfistcr, X.; Cane de Andrade, M.C.: Laffitte, J.A. Tefrahedron : Asymmetry. 1994.5, 665-674: d) GenC, J.-P.; Pinel. C.: Ratovelomanana-Vidal. V.; Mallart, S.; Pfister, X.; Bischoff, L.; Cairo de Andrade, MC.; Dames, S.; Galopin, C.; Lalfitte, J.A. Tetrahedron : Asymmetry. 1994.5, 675-690. a) GenCt, J.-P.: Mallan, S.; Jug& S., French Patent no 8911159 (August 1989); b) Gent%, J.-P.; Pinel, C.; Mallart. S.; Jug& S.; Thorimbert, S.; Laffitte, J.A. Tetrahedron : Asymmerry 1991.2, 555-567; c) Gem%, J.-P.; Ptister, X.; Ratovelomanana-Vidal, V.; Pinel, C.; Laffitte, J.A. Tefrahedron Left. 1994.35.4559-4562; d) For leading references in this area see: Noyori, R.; Ike&, T.; Okhuma, T.; Widhalm, M.; Kitamura, M.; Takaya, H.; Akutagawa, S.: Sayo. N.; Saito, T.; Takemoti. T.: Kumobayashi, H. J. Am. Chem. Sot. 1989,111, 9134-9135 and Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Sot. 1993,115, 144-152. a) For microbial asymmetric reduction of a-chloro$-keto esters see : Akita. H.; Matsukura, H.; Oishi, T.; Tetrahedron Leu. 1986,44,5397-5400; b) Cabon, 0.; Larcheveque, M.; Buisson, D.; Azerad, R. Terrahedron ,Qtr. 1992.33, 7337-7340; c) Akita, H.; Todoroki, R.; Endo, H.; Ikari, Y.; Oishi, T. Synthesis. 1993.5, 513-516. General procedure of hydrogenation: 2-chloro-3-keto esters (1 mmol) dissolved in 2 ml of anhydrous solvent were. degassed by a 3 times cycle of vacuum/argon at R.T.. This solution was transfcrcd into a 10 ml Schlenck tube filled with argon atmosphere containing (COD)Ru(2-methylally1)2 (1 equiv.) and the chiral diphosphine (1.3 cquiv.). The reaction mixture was immediately placed into an autoclave which was purged 3 times with hydrogen and pmssuriscd. Commercially available from Acres Organics.
(Received in France 8 December 1994; accepted 25 January 1995)