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First enantioselective addition of dialkylzinc to ketones promoted by titanium(IV) derivatives
Pergamon
Tetrahedron Letters 39 (1998) 1239-1242
TETRAHEDRON LETTERS
First Enantioselective Addition of Dialkylzinc to Ketones Promoted by Titanium(IV) Derivatives D i e g o J. R a m 6 n a n d M i g u e l Y u s *
Departamentode QuimicaOrg~mica,Facoltadde Ciencias,Universidadde Alicante,Apdo.99, 03080 Alieante,Spain Fax: +34-6-5903549,Email:[email protected] Received 16 October 1997; revised 1 December 1997; accepted 5 December 1997 Abstract: The reaction of dimethyl or diethylzinc with ketones in the presence of a stoichiometric
amount of titanium tetraisopropoxide and a catalytic amount (20 tool %) of camphorsulfonamide
derivatives as chiral ligandsleads to the formationof the correspondingenantioenrichedalcohols with enantiomericratios up to 94.5:5.5, the best resultsbeingobtainedwhenpbenonesare used as substrates independentlyof the zincreagent. © 1998ElsevierScienceLtd. All rightsreserved.
Asymmetric control in the reaction of organometallics with carbonyl compounds presents a focused challenge of substantial general interest. The modulation of organometallics such as organolithium, t organolanthanide,2 organostannane,3 organosilane,4 ~_rldorganochromium5 derivatives by a chiral modification has been well documented when an aldehyde is used as the electrophilic carbonyl compound. Thus, the stereoselective addition of dialkylzincs to one of the two heterotopic faces of an aldehyde, promoted mainly by chiral aminoalcohols6 or chiral titanium derivatives,7 is probably the most studied process. However, although a large number of biologically active natural products contain quatemary carbon atoms,8 the asymmetric synthesis of tertiary alcohols by addition of carbon nucleophiles to ketones has achieved considerably less success using chiral ligands.9 The enantioselective addition of unreactive organometallics, such as dialkylzincs, to ketones in the presence of chiral aminoalcohols failed,lO making this subject an open challenge. On one hand, it is known that alkyltitanium(IV) alkoxides add smoothly to ketones at room temperature, t 1 giving the expected tertiary carbinols. In addition, some chiral titanium(IV) alkoxide has been successfully used as Lewis acid in the catalytic reduction of ketones to obtain enantioenriched secondary alcohols. 12 On the other hand, we have recently reported a new class of chiral bidentate ligands (1) derived from camphorsulfonamide,t3 that showed the highest enantioselectivity in the addition of diethylzinc to benzaldehyde in the presence of titanium tetraisopropoxide at room temperature. These both considerations prompted us to study the possibility of promoting the enantioselective addition of dialkylzinc to ketones in the presence of a titanium alkoxide and using the mentioned chiral ligand. In this communication we report the, to the best of our knowledge, first enantioselective addition of dialkylzinc to ketones.
RI= OH, R2=H, R3=benzyl lb: RI= OH, R2=H, R3=1-naphthylmethyl lc: RI= H, R2=OH, R3=1-naphthylmethyl la:
R3NHSO2~R2 R1
0040-4039/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved. PII: S0040-4039(97)10765-1
1240
The addition of diethylzinc to acetophenone at room temperature took place in the presence of a catalytic amount of the camphorsulfonamide derivative l a and an excess of titanium tetraisopropoxide after two days with 56% yield and an enantiomeric ratio (e.r.) of 88.5:11.5 (Table 1, entry 1). In a subsequent series of experiments acetophenone and diethylzinc were chosen as the standard reagents in order to optimise the reaction conditions. Thus, when the reaction was carried out at higher temperature (60°C) the e.r. decreased a little bit, giving a similar chemical yield (Table 1, entry 2). At lower temperatures (4 or -15°C) the e.r. increased up to 92.0:8.0 (Table 1, entries 1, 3 and 4); however, whereas the enantioselectivity was similar at 4 or -15°C, the chemical yield at the last temperature was lower (11%), starting acetophenone being recovered (45%) after 12 days. When the reaction was carried out at room temperature but using a stoichiometric amount of the ligand 1 a the e.r. was a little bit better, the chemical yield being increased up to 89% in only one day (Table 1, entries 1 and 5). This result would indicate that the slowest step in the addition involves the presence of the hydroxysulfonamide ligand at the titanium center. Finally, the use of other camphorsulfonamide derivatives 1 b and le and the effect of the presence of calcium hydride was tested: the use of a more crowded ligand such as l b gave better yields and after a shorter reaction time (Table I, entries 3 and 6). On the other hand, the deprotonation of the hydroxysulfonamide ligand with calcium hydride 7a made the reaction slower but the e.r. was increased (Table 1, entries 6 and 7). Ligand lc, having the hydroxy group in the endo position, gave very poor chemical yield and e.r. (Table 1, entry 8); the same behaviour was observed when benzaldehyde was used as electrophilic reagent.23 Once the conditions for the enantioselective addition of diethylzinc to acetophenone were optimised (Table 1, entry 7), other ketones were submitted to the enantioselective addition of dimethyl and diethylzinc. The reactions with dimethylzinc took longer, the e.r. being similar to the same processes using diethylzinc (Table I, entries 9, 10 and 11). When a bulky ketone such as tert-butyl methyl ketone was used, the reaction occurred only a high temperatures (60°C) yielding a racemic mixture of the corresponding tertiary alcohol (Table 1, entry 12). In the case of ct-tetralone the chemical yield was poor (25%) and did not improve with longer reaction times, the e.r. being however one of the best in this series (Table 1, entry 13). When an o~,13-unsaturated ketone, such as 1-cyclohexenyl methyl ketone, was used as carbonyl component, both chemical yield and e.r. dropped down (Table 1, entry 14).
OH
2: 3: 4: 5:
RI= RI= RI= RI=
Me, R2= Et Me, R2= Bun Et, R2= Bun Me, R2= Bu t
Et OH
6
OH
7
In conclusion, we have described here a practical method for the enantioselective additon of dialkylzinc reagents to ketones. It must be pointed out that the preferential addition to methyl or ethyl aryl ketones occurred from the Si-face independently of the dialkylzinc reagent; however, in the case of valerophenone the addition took place from the Re-face in all cases. Work is underway in order to propose a model for the rationalisation of the present results.
1241
Table 1. Enantioselective Addition of Dialkylzinc to Ketones
0 \.II,./
Ti(OPri)4, 1 (eat.) +
:
Reaction conditions T (°C)
t (d)
OH
Product
Entry
R
Ligand
Ketone
No. Yield (%)a
e.r.b
[t~]ort (C)C
Conf.
1
Et
la
PhCOMe
25
2
2
56
88.5:11.5
S
2
Et
la
PhCOMe
60
0.1
2
58
86.0:14.0
S
3
Et
1a
PhCOMe
4
5
2
60
92.0:8.0
S
4
Et
la
PhCOMe
-15
12
2
11
91.0:9.0
S
5
Et
lad
PhCOMe
25
1
2
89
90.0:10.0
S
6
Et
1b
PhCOMe
4
4
2
85
91.0:9.0
S
71
93.0:7.0
7e
Et
1b
PhCOMe
4
4
2
8e
Et
1c
PhCOMe
4
4
2
9e
IVle
lb
PhCOEt
4
14
2
10e
Me
lb
PhCOBun
4
17
4g
-9.2 (3.2)f
S
67.0:33.0
S
89
5.5:94.5
R
3
95
91.5:8.5
+7.1 (3.7)h
R
78
93.0:7.0
-1.8 (2.4)i
R
lle
Et
lb
PhCOBun
4
6
4
12e
Me
lb
PhCOBu t
60
2
5
13e
El:
lb
~-tetralone
4
14
6
25
5.5:94.5
-1.6 (2.3)i
-J
14e
El
lb
4
6
7
36
75.5:24.5
+0.7 (3.0)/
-J
_k
3s
50.0:50.0
Isolated yield based on the starting ketone, b Enantiomeric ratios were determined by GLC analysis on 13cyclodextrin capillary column and are given following the elution order, c Concentration (g/100 ml) is given in parenthesis, d A stoichiometric amount of the ligand was used. e Calcium hydride (1:0.4 molar ratio) was used as base. YIn chloroform, g GLC yield, h In acetone, i In methanol. J Not determined, k 1-Cyclohexenyl methyl ketone was used. a
In a typical procedure to a solution of the ligand l b (1 mmol, 0.38 g) in toluene (15 ml) was added calcium hydride (0.1 g, 2.4 mmol) and the mixture was stirred ca. 2 h at room temperature under argon. Then, titanium isopropoxide (1.9 ml, 6.5 mmol) was added, the mixture was cooled to 0°C and diethylzinc (6 ml 2 M in toluene, 12 mmol) and acetophenone (0.59 ml, 5 mmol) were successively added. The resulting mixture was placed into the refrigerator and after 4 d was successively quenched with methanol (2 ml) and a saturated solution of ammonium chloride (20 ml). The resulting mixture was filtered through celite, extracted with ethyl acetate (3 x 50 ml) and the organic layer dried over anhydrous sodium sulfate. Solvents were removed under reducted pressure (15 Torr) and the resulting residue was distilled bulb to bulb (0.1 Torr, 110°C) to give crude compound 2 (0.61g), which contained ca. 12% acetophenone (GLC). Pure compound 2 was isolated after flash chromatography (silica gel, hexane/ethyl acetate): 0.53 g (71%), e.r.: 93.0/7.0; [Ct]Drt-9.2 (C = 3.2, CHC13). ACKNOWLEDGEMENTS
This work was finantially supported by the DGICYT (no. PB94-1514) from the Spanish Ministry of Education and Culture (MEC). D.J.R. thanks the MEC for a postdoctoral fellowship.
1242
REFERENCES AND NOTES
1. (a) Mukaiyama, T.; Suzuki, K.; Soai, K.; Sato, T. Chem. Lett. 1979, 447-448. (b) Mukaiyama, T.; Suzuki, K. Chem- Lett. 1980, 255-256. (c) Itsuno, S.; Sasaki, M.; Kuroda, S.; Ito, K. Tetrahedron: Asymmetry 1995, 6, 1507-1510. (d) Jones, C. A.; Jones, I. G.; North, M.; Pool, C. R. Tetrahedron Lett. 1995, 36, 7885-7888. (e) Corruble, A.; Valnot, J.-Y.; Maddaluno, J.; Duhamel, P. Terfahedron: Asymmetry 1997, 8, 1519-1523. 2. (a) Chibale, K.; Greeves, N.; Lyford, L.; Pease, J. E. Tetrahedron: Asymmetry 1993, 4 , 2407-2410. (b) Greeves, N.; Pease, J. E.; Bowden, M. C.; Brown, S. M. Tetrahedron Lett. 1996, 37, 2675-2678. (c) Greeves, N.; Pease, J. E. Tetrahedron Lett. 1996, 37, 5821-5824. (d) Arai, T.; Yamada, Y. M. A.; Yamamoto, N.; Sasai, H.; Shibasaki, M. Chem. Eur. J. 1996, 2, 1368-1372. 3. (a) Costa, A. L.; Piazza, M. G.; Tagliavini, E.; Trombini, C.; Umani-Ronchi, A. J. Am. Chem. Soc. 1993, 115, 7001-7002. (b) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem- Soc. 1993, 115, 8467-8468. (c) Keck, G. E.; Geraci, L. S. Tetrahedron Lett. 1993, 34, 7827-7828. (d) Keck, G. E.; Krishnamurthy, D.; Grier, M. C. J. Org. Chem- 1993, 58, 6543-6544. (e) Keck, G. E.; Krishnamurthy, D.; Chen, X. Tetrahedron Lett. 1994, 35, 8323-8324. (f) Bedeschi, P.; Casolari, S.; Costa, A. L.; Tagliavini, E. Tetrahedron Lett. 1995, 36, 7897-7900. (g) Yu, C.-M.; Choi, H.-S.; Jung, W.-H.; Lee, S.-S. Tetrahedron Lett. 1996, 37, 7095-7098. (h) Yanagisawa, A.; Nakashima, H.; Ishiba, A.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 4723-4724. (i) Keck, G. E.; Krishnamurthy, D. J. Org. Chem. 1996, 61, 7638-7639. (j) Weigand, S.; B~ckner, R. Chem. Eur. J. 1996, 9, 1077-1084. (k) Cozzi, P. G.; Orioli, P.; Tagliavini, E.; Umani-Ronchi, A. Tetrahedron Lett. 1997, 38, 145-148. (1) Lipshutz, B. H.; James, B.; Vance, S.; Carrico, I. Tetrahedron Lett. 1997, 38, 753-756. 4. (a) Ishihara, K.; Mouri, M.; Gao, Q.; Murayama, T.; Furuta, K.; Yamamoto, H. J. Am. Chem. Soc. 1993, 115, 11490-11495. (b) Iseki, K.; Nagai, T.; Kobayashi, Y. Tetrahedron Lett. 1994, 35, 31373138. (c) Denmark, S. E.; Coe, D. M.; Pratt, N. E.; Griedel, B. D. J. Org. Chem. 1994, 59, 61616163. (d) Gauthier, D. R., Jr.; Carreira, E. M. Angew. Chem. Int. Ed. Engl. 1996, 35, 2363-2365. (e) Wang, Z.; Wang, D.; Sui, X. J. Chem. Soc., Chem. Commun. 1996, 2261-2262. 5. Sugimoto, K.; Aoyagi, S.; Kibayashi, C. J. Org. Chem. 1997, 62, 2322-2323. 6. (a) Noyori, R.; Kitamura, M. Angew. Chem. Int. Ed. Engl. 1991, 30, 49-69. (b) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833-856. 7. For some recent accounts, see: (a) Ito, K.; Kimura, Y.; Okamura, H.; Katsuki, T. Synlett 1992, 573574. (b) Qiu, J.; Guo, C.; Zhang, X. J. Org. Chem. 1997, 62, 2665-2668. (c) Seebach, D.; Beck, A. K. Chimia 1997, 51,293-297. (d) Berger, S.; Langer, F.; Lutz, C.; Knochel, P.; Mobley, T. A.; Reddy, C. K. Angew. Chem. Int. Ed. Engl. 1997, 36, 1496-1498. (e) Mori, M.; Nakai, T. Tetrahedron Lett. 1997, 38, 6233-6236. 8. Fuji, K. Chem. Rev. 1993, 93, 2037-2066. 9. For enantioselective addition of Grignard reagents,4a-e organolithium compounds4f-hor allylzinc halides4i to ketones or ketone derivatives by chiral ligand modulation, see: (a) Cohen, H. L.; Wright, G. F. J. Org. Chem. 1953, 18, 432-446. (b) Inch, T. D.; Lewis, G. J.; Sainsbury, G. L.; Sellers, D. J. Tetrahedron Lett. 1969, 3657-3660. (c) Meyers, A. I.; Ford, M. E. Tetrahedron Lett. 1974, 1341-1344. (d) Weber, B.; Seebach, D, Angew. Chem. Int. Ed. Engl. 1992, 31, 84-86. (e) Weber, B.; Seebach, D. Tetrahedron 1994, 50, 6117-6128. (f) Nozaki, H.; Aratani, T.; Toraya, T.; Noyori, R. Tetrahedron 1971, 27, 905913. (g) Huffman, M. A.; Yasuda, N.; DeCamp, A. E.; Grabowski, E. J. J. J. Org. Chem. 1995, 60, 1590-1594. (h) Thompson, A. S.; Corley, E. G.; Hutington, M. F.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 8937-8940. (i) Hanessian, S.; Yang, R.-Y. Tetrahedron Lett. 1996, 37, 8997-9000. 10. (a) Noyori, R.; Suga, S.; Kawai, K.; Okada, S.; Kitamura, M.; Oguni, N.; Kaneko, T.; Matsuda, Y. J. Organomet. Chem. 1990, 382, 19-37. (b) Watanabe, M.; Soai, K. J. Chem. Soc., Perkin Trans. 1 1994, 3125-3128. 11. (a) Seebach, D.; Weidmann, B.; Widler, L. In Modern Synthetic Methods, Scheffold, R. Ed.; Verlag Sauerlander: Aarau, 1983; pp. 217-353. (b) Reetz, M. T.; Westermann, J.; Steinbach, R.; Wenderoth, B.; Peter, R.; Ostarek, R.; Maus, S. Chem. Ber. 1985, 118, 1421-1440. (c) Reetz, M. T.; Steinbach, R.; Westermann, J.; Peter, R.; Wenderoth, B. Chem. Ber. 1985, 118, 1441-1454. (d) Dimitrov, V.; Stanchev, S.; Milenkov, B.; Nikiforov, T.; Demirev, P. Synthesis 1991, 228-232. 12. (a) Lindsley, C. W.; DiMare, M. Tetrahedron Lett. 1994, 35, 5141-5144. (b) Giffels, G.; Dreisbach, C.; Kragl, U.; Weigerding, M.; Waldmann, H.; Wandrey, C. Angew. Chem. Int. Ed Engl. 1995, 34, 20052006. (c) Imma, H.; Mori, M.; Nakai, T. Synlett 1996, 1229-1230. (d) Almqrist, F.; Torstensson, L.; Gudmundsson, A.; Frejd, F. Angew. Chem. Int. Ed. Engl. 1997, 36, 376-377. 13. Ram6n, D. J.; Yus, M. Tetrahedron: Asymmetry 1997, 8, 2479-2496.
Tetrahedron Letters 39 (1998) 1239-1242
TETRAHEDRON LETTERS
First Enantioselective Addition of Dialkylzinc to Ketones Promoted by Titanium(IV) Derivatives D i e g o J. R a m 6 n a n d M i g u e l Y u s *
Departamentode QuimicaOrg~mica,Facoltadde Ciencias,Universidadde Alicante,Apdo.99, 03080 Alieante,Spain Fax: +34-6-5903549,Email:[email protected] Received 16 October 1997; revised 1 December 1997; accepted 5 December 1997 Abstract: The reaction of dimethyl or diethylzinc with ketones in the presence of a stoichiometric
amount of titanium tetraisopropoxide and a catalytic amount (20 tool %) of camphorsulfonamide
derivatives as chiral ligandsleads to the formationof the correspondingenantioenrichedalcohols with enantiomericratios up to 94.5:5.5, the best resultsbeingobtainedwhenpbenonesare used as substrates independentlyof the zincreagent. © 1998ElsevierScienceLtd. All rightsreserved.
Asymmetric control in the reaction of organometallics with carbonyl compounds presents a focused challenge of substantial general interest. The modulation of organometallics such as organolithium, t organolanthanide,2 organostannane,3 organosilane,4 ~_rldorganochromium5 derivatives by a chiral modification has been well documented when an aldehyde is used as the electrophilic carbonyl compound. Thus, the stereoselective addition of dialkylzincs to one of the two heterotopic faces of an aldehyde, promoted mainly by chiral aminoalcohols6 or chiral titanium derivatives,7 is probably the most studied process. However, although a large number of biologically active natural products contain quatemary carbon atoms,8 the asymmetric synthesis of tertiary alcohols by addition of carbon nucleophiles to ketones has achieved considerably less success using chiral ligands.9 The enantioselective addition of unreactive organometallics, such as dialkylzincs, to ketones in the presence of chiral aminoalcohols failed,lO making this subject an open challenge. On one hand, it is known that alkyltitanium(IV) alkoxides add smoothly to ketones at room temperature, t 1 giving the expected tertiary carbinols. In addition, some chiral titanium(IV) alkoxide has been successfully used as Lewis acid in the catalytic reduction of ketones to obtain enantioenriched secondary alcohols. 12 On the other hand, we have recently reported a new class of chiral bidentate ligands (1) derived from camphorsulfonamide,t3 that showed the highest enantioselectivity in the addition of diethylzinc to benzaldehyde in the presence of titanium tetraisopropoxide at room temperature. These both considerations prompted us to study the possibility of promoting the enantioselective addition of dialkylzinc to ketones in the presence of a titanium alkoxide and using the mentioned chiral ligand. In this communication we report the, to the best of our knowledge, first enantioselective addition of dialkylzinc to ketones.
RI= OH, R2=H, R3=benzyl lb: RI= OH, R2=H, R3=1-naphthylmethyl lc: RI= H, R2=OH, R3=1-naphthylmethyl la:
R3NHSO2~R2 R1
0040-4039/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved. PII: S0040-4039(97)10765-1
1240
The addition of diethylzinc to acetophenone at room temperature took place in the presence of a catalytic amount of the camphorsulfonamide derivative l a and an excess of titanium tetraisopropoxide after two days with 56% yield and an enantiomeric ratio (e.r.) of 88.5:11.5 (Table 1, entry 1). In a subsequent series of experiments acetophenone and diethylzinc were chosen as the standard reagents in order to optimise the reaction conditions. Thus, when the reaction was carried out at higher temperature (60°C) the e.r. decreased a little bit, giving a similar chemical yield (Table 1, entry 2). At lower temperatures (4 or -15°C) the e.r. increased up to 92.0:8.0 (Table 1, entries 1, 3 and 4); however, whereas the enantioselectivity was similar at 4 or -15°C, the chemical yield at the last temperature was lower (11%), starting acetophenone being recovered (45%) after 12 days. When the reaction was carried out at room temperature but using a stoichiometric amount of the ligand 1 a the e.r. was a little bit better, the chemical yield being increased up to 89% in only one day (Table 1, entries 1 and 5). This result would indicate that the slowest step in the addition involves the presence of the hydroxysulfonamide ligand at the titanium center. Finally, the use of other camphorsulfonamide derivatives 1 b and le and the effect of the presence of calcium hydride was tested: the use of a more crowded ligand such as l b gave better yields and after a shorter reaction time (Table I, entries 3 and 6). On the other hand, the deprotonation of the hydroxysulfonamide ligand with calcium hydride 7a made the reaction slower but the e.r. was increased (Table 1, entries 6 and 7). Ligand lc, having the hydroxy group in the endo position, gave very poor chemical yield and e.r. (Table 1, entry 8); the same behaviour was observed when benzaldehyde was used as electrophilic reagent.23 Once the conditions for the enantioselective addition of diethylzinc to acetophenone were optimised (Table 1, entry 7), other ketones were submitted to the enantioselective addition of dimethyl and diethylzinc. The reactions with dimethylzinc took longer, the e.r. being similar to the same processes using diethylzinc (Table I, entries 9, 10 and 11). When a bulky ketone such as tert-butyl methyl ketone was used, the reaction occurred only a high temperatures (60°C) yielding a racemic mixture of the corresponding tertiary alcohol (Table 1, entry 12). In the case of ct-tetralone the chemical yield was poor (25%) and did not improve with longer reaction times, the e.r. being however one of the best in this series (Table 1, entry 13). When an o~,13-unsaturated ketone, such as 1-cyclohexenyl methyl ketone, was used as carbonyl component, both chemical yield and e.r. dropped down (Table 1, entry 14).
OH
2: 3: 4: 5:
RI= RI= RI= RI=
Me, R2= Et Me, R2= Bun Et, R2= Bun Me, R2= Bu t
Et OH
6
OH
7
In conclusion, we have described here a practical method for the enantioselective additon of dialkylzinc reagents to ketones. It must be pointed out that the preferential addition to methyl or ethyl aryl ketones occurred from the Si-face independently of the dialkylzinc reagent; however, in the case of valerophenone the addition took place from the Re-face in all cases. Work is underway in order to propose a model for the rationalisation of the present results.
1241
Table 1. Enantioselective Addition of Dialkylzinc to Ketones
0 \.II,./
Ti(OPri)4, 1 (eat.) +
:
Reaction conditions T (°C)
t (d)
OH
Product
Entry
R
Ligand
Ketone
No. Yield (%)a
e.r.b
[t~]ort (C)C
Conf.
1
Et
la
PhCOMe
25
2
2
56
88.5:11.5
S
2
Et
la
PhCOMe
60
0.1
2
58
86.0:14.0
S
3
Et
1a
PhCOMe
4
5
2
60
92.0:8.0
S
4
Et
la
PhCOMe
-15
12
2
11
91.0:9.0
S
5
Et
lad
PhCOMe
25
1
2
89
90.0:10.0
S
6
Et
1b
PhCOMe
4
4
2
85
91.0:9.0
S
71
93.0:7.0
7e
Et
1b
PhCOMe
4
4
2
8e
Et
1c
PhCOMe
4
4
2
9e
IVle
lb
PhCOEt
4
14
2
10e
Me
lb
PhCOBun
4
17
4g
-9.2 (3.2)f
S
67.0:33.0
S
89
5.5:94.5
R
3
95
91.5:8.5
+7.1 (3.7)h
R
78
93.0:7.0
-1.8 (2.4)i
R
lle
Et
lb
PhCOBun
4
6
4
12e
Me
lb
PhCOBu t
60
2
5
13e
El:
lb
~-tetralone
4
14
6
25
5.5:94.5
-1.6 (2.3)i
-J
14e
El
lb
4
6
7
36
75.5:24.5
+0.7 (3.0)/
-J
_k
3s
50.0:50.0
Isolated yield based on the starting ketone, b Enantiomeric ratios were determined by GLC analysis on 13cyclodextrin capillary column and are given following the elution order, c Concentration (g/100 ml) is given in parenthesis, d A stoichiometric amount of the ligand was used. e Calcium hydride (1:0.4 molar ratio) was used as base. YIn chloroform, g GLC yield, h In acetone, i In methanol. J Not determined, k 1-Cyclohexenyl methyl ketone was used. a
In a typical procedure to a solution of the ligand l b (1 mmol, 0.38 g) in toluene (15 ml) was added calcium hydride (0.1 g, 2.4 mmol) and the mixture was stirred ca. 2 h at room temperature under argon. Then, titanium isopropoxide (1.9 ml, 6.5 mmol) was added, the mixture was cooled to 0°C and diethylzinc (6 ml 2 M in toluene, 12 mmol) and acetophenone (0.59 ml, 5 mmol) were successively added. The resulting mixture was placed into the refrigerator and after 4 d was successively quenched with methanol (2 ml) and a saturated solution of ammonium chloride (20 ml). The resulting mixture was filtered through celite, extracted with ethyl acetate (3 x 50 ml) and the organic layer dried over anhydrous sodium sulfate. Solvents were removed under reducted pressure (15 Torr) and the resulting residue was distilled bulb to bulb (0.1 Torr, 110°C) to give crude compound 2 (0.61g), which contained ca. 12% acetophenone (GLC). Pure compound 2 was isolated after flash chromatography (silica gel, hexane/ethyl acetate): 0.53 g (71%), e.r.: 93.0/7.0; [Ct]Drt-9.2 (C = 3.2, CHC13). ACKNOWLEDGEMENTS
This work was finantially supported by the DGICYT (no. PB94-1514) from the Spanish Ministry of Education and Culture (MEC). D.J.R. thanks the MEC for a postdoctoral fellowship.
1242
REFERENCES AND NOTES
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