Synthesis of Poly(Ethylene Glycol)–Supported (R)-BINOL Derivatives and Their First Application in Enantioselective Mukaiyama Aldol Reactions

Abstract

The Mukaiyama aldol reaction of 2-styryl-oxazole-4-carbaldehyde (1) as model substrate with S-ketene silyl acetal 2 catalyzed by poly(ethylene glycol)-supported binaphthyl-derived chiral titanium(IV) complexes afforded the corresponding aldol product in good to excellent yields and enantioselectivities up to 94% ee. The chemical yields and/or the enantioselectivities are enhanced by generating the active catalyst from Ti(OiPr)₄, polymer-supported ligands (R)-6 or (R)-8, and chiral or achiral promoters. Pyrrolidine derivative (S)-13 and trifluoromethyl-substituted phenol 12 are the most efficient additives found.

Keywords:

• Aldol reaction
• asymmetric catalysis
• binaphthalene
• chiral additives
• poly(ethylene glycol)
• polymer-supported reaction
• thioester

Recently, asymmetric versions of carbon–carbon bond-forming processes using chiral polymer-supported catalysts have been intensively investigated.^{[ 1 ]} In particular, the advantages of soluble polymers such as poly(ethylene glycol) (PEG) and its mono methyl ether (MPEG) have been explored as supports for catalyst immobilization and have led to a steadily increasing number of applications.^{[ 2 ]} These polymers can be equipped with a variety of spacers or reactive groups and are inexpensive, thermally stable, easy to recover, and soluble in many organic solvents. On the other hand, among the large number of ligands being subjected to asymmetric syntheses, C₂-symmetric 1,1′-binaphthyl-2,2′-diol (abbreviated as BINOL) and its derivatives have occupied a prominent position.^{[ 3 ]} Recently, a number of immobilized soluble or insoluble BINOL derivatives have been synthesized, and the resulting polymer-supported BINOL complexes were applied in asymmetric transformations such as aza Diels–Alder reactions,^{[ 4 ]} additions of diethyl zinc to aldehydes,^{[ 5 ]} carbonyl-ene reactions,^{[ 6 ]} sulfoxidation reactions,^[5d,6,7] Strecker-type reactions,^{[ 8 ]} Michael additions,^{[ 9 ]} 1,3-dipolar cycloadditions,^[5d] epoxidations,^{[ 9 10 ]} and other transformations.^{[ 11 ]} To the best of our knowledge, at present only a few contributions have been reported that deal with soluble PEG-supported catalysts for asymmetric Mukaiyama aldol reactions.^{[ 12 ]} Reflecting the potential utility of the Mukaiyama process^{[ 13 ]} in the synthesis of compounds of biological importance and based on the experience of other groups,^[ 14-21 ^] we have already reported an efficient method for enantioselective additions of S-ketene silyl acetal 2 to various carbonyl compounds employing a catalyst without polymer support.^{[ 22 , 23 ]} In the present study, we focus our attention on the preparation of MPEG-supported BINOL ligands and their efficacy as BINOLate–titanium catalysts in enantioselective aldol reactions. As a model reaction, we have chosen the aldol reaction of S-ketene silyl acetal 2 with 2-styryl-oxazole-4-carbaldehyde (1), resulting in the enantioselective formation of aldol product 3, which is a known intermediate in the total synthesis of the marine natural product phorboxazole B [Eq. (1)].^{[ 24 ]}

We selected MPEG with an average molecular weight of 5000 as support. While the BINOL ligand can be attached to a polymer by linkage at several positions of the naphthalene framework, we decided to use the 6-position. We choose this position to avoid the connection of the polymer moiety in close proximity of the 2- and 2′-positions, which bind the titanium counterpart in the active catalyst species. The preparation of the desired polymer-supported BINOL ligands (R)-6 and (R)-8 was easily achieved by a Heck coupling reaction of MPEG-supported acrylate 5 ^{[ 25 ]}with the corresponding 6-bromo- and 6,6′-dibromo-substituted precursors (R)-4 ^{[ 26 ]} and (R)-7,^{[ 27 ]} respectively (Scheme 1). The expected coupling products were formed in good yields and with a fairly low degree of racemization. The third polymer-supported BINOL ligand, (R)-9, was obtained in excellent yield by hydrogenation of (R)-6. In contrast to similar coupling reactions of the enantiomer of (R)-4 with butyl acrylate,^{[ 26 ]} we observed only moderate racemization of the coupling products. Considering the reported racemization, we cleaved the ester unit in (R)-6 by treatment with potassium hydride (KOH) in THF/H₂O at rt overnight resulting in the formation of the literature known acid.^[26b] We then compared the [α]_D value of the sample with those of the literature. The ee value of the acrylic acid derivative was in the range of 90–95%. On the other hand, the cross-coupling reaction performed at a longer reaction time (ca. 48 h) and lower catalyst loading (ca. 5 mol%) was higher yielding, but the enantiomeric excess decreased to ca. 70–80% ee. The corresponding doubled coupled product in the coupling reaction of (R)-7 and 5 could not be observed.

Scheme 1 Preparation of polymer-supported BINOL derivatives (R)-6 and (R)-8 by Heck coupling reactions and BINOL derivative (R)-9 by subsequent hydrogenation.

Scheme 2 Additives used in the aldol reaction of 1 and 2.

The chiral polymer-supported BINOL derivatives (R)-6, (R)-8, and (R)-9 were evaluated as ligands in the titanium-catalyzed aldol reaction of 2-styryl-oxazole-4-carbaldehyde (1) with S-ketene silyl acetal 2, which furnished the silylated aldol addition product 10 as a major component [Eq. (2)]. The results are summarized in Table 1 with entry 1 as reference experiment, employing (R)-BINOL without polymer support.^{[ 22 ]} Our initial efforts focused on the optimization of this aldol reaction in terms of solvents, amount of catalyst, and temperature effects. The first experiments were carried out analogously to a procedure described by Keck and Krishnamurthy.^{[ 28 ]} The (R)-BINOL-Ti catalyst was generated in situ by mixing the corresponding polymer-supported BINOL ligand (R)-6, (R)-8, or (R)-9 and Ti(OiPr)₄ in a ratio of 1:1 at room temperature in the solvent indicated in Table 1. The solvent strongly affected the reaction: halogenated solvents such as dichloromethane and chloroform provided the aldol product in high yields and good enantioselectivities, whereas tetrahydrofuran (THF), toluene, and trifluoromethylbenzene gave moderate to good yields but only poor enantioselectivities (see, entries 2–7). The reduction of the quantity of the premixed catalyst from 15 to 10 mol% essentially did not influence the yield and selectivity of the aldol addition (see entries 5 and 8). Even lower catalyst loading may be possible. However, most of the aldol reactions described herein were carried out with 10 mol% of catalyst. Alternatively, the generation of the catalyst was performed by mixing of 2 equivalents of BINOL ligand (R)-8 and 1 equivalent of Ti(OiPr)₄, a procedure which was already described as a variation in the Keck paper.^{[ 14 ]} In this case, we obtained a result very similar to that induced by the 1:1 mixture (see entries 8 and 9). Comparison of BINOL-ligands (R)-6, (R)-8, and (R)-9 revealed that the aldol reaction with compound (R)-6 gave the highest enantioselectivity with 78% ee (see entries 3, 5, and 10). The chemical yields were in all cases excellent, generally exceeding 90%. Starting the aldol reaction at lower temperature (0 °C for 8 or 14 h), followed by warming up to room temperature for an additional day, caused an improvement of stereoselectivity. An increase from 78% to 90% ee was observed for (R)-6 (compare entries 3 and 11) and from 50% to 61% ee for (R)-8 (compare entries 5 and 12). In the case of (R)-6, we isolated the desilylated product 3 in 6% yield beside the silylated aldol adduct 10 (64% yield). The results obtained under optimized conditions (entry 11, Table 1) compare very well with the previously reported values obtained for the aldol reaction with (R)-BINOL as ligand without polymeric support (entry 1, Table 1).^{[ 22 ]} Most gratifyingly, the chemical yields as well as the enantioselectivity are almost at the same level. Noteworthy is that the PEG-supported ligand (R)-6 was readily recovered by precipitation with diethyl ether followed by filtration, and it could be reused at least twice according to the conditions given in entry 3 (Table 1) with a moderate loss of enantioselectivity (from 78% to 70% ee). However, a decrease in chemical yield (from 93% to 35%) was observed.

Table 1. Aldol reactions of aldehyde with S-ketene silyl acetal under Ti(OiPr)₄/(R)-BINOL , , and catalysis (Eq. 2)

Entry	Ligand	Amount of catalyst	Reaction conditions	Yield of 10	Yield of 3	Ee ^a
1 ^b	(R)-BINOL	10 mol%	Et2 O, a) 0 °C, 5 h; b) rt, 16 h	11%	76%	95%
2	(R)-6	15 mol%	THF, rt, 2 d	50%	—	35%
3	(R)-6	10 mol%	CHCl3, rt, 1 d	93%	—	78%
4	(R)-6	10 mol%	CH2Cl2, rt, 1 d	91%	—	76%
5	(R)-8	10 mol%	CH2Cl2, rt, 1 d	95%	—	50%
6	(R)-8	10 mol%	Toluene, rt, 5 d ^c	16%	14%	32%
7	(R)-8	15 mol%	Trifluoromethylbenzene, rt, 3 d	26%	—	15%
8	(R)-8	15 mol%	CH2Cl2, rt, 1 d	92%	—	51%
9	(R)-8	13 mol% ^d	CH2Cl2, rt, 1 d	97%	—	55%
10	(R)-9	10 mol%	CH2Cl2, rt, 1 d	96%	—	70%
11	(R)-6	10 mol%	CH2Cl2, a) 0 °C, 8 h; b) rt, 1 d	64%	6%	90%
12	(R)-8	15 mol%	CH2Cl2, a) 0 °C, 14 h; b) rt, 1 d	96%	—	61%

Next, we explored the influence of various additives on the model aldol reaction. It is well known that combinations of BINOL derivatives with achiral and chiral promoters are useful in several asymmetric carbon–carbon bond-forming processes.^{[ 4 , 22 , 23 ,} 29-31 ^] These additives either enhance the enantioselectivity and/or the reactivity (chemical yield). Representative examples of these experiments are summarized in Table 2, which should be compared to the results without additives (entries 1 and 2). The use of additives in the aldol reaction of 1 and 2 generally caused longer reaction times, and frequently mixtures of silylated and desilylated aldol products 10 and 3 were obtained, which could easily be separated by column chromatography. As a consequence, the yields are often lower than in reactions without additives.

Table 2. Aldol reactions of aldehyde with S-ketene silyl acetal under Ti(OiPr)₄/(R)-BINOL and catalysis in the presence of additives

Entry	Ligand ^a	Reaction conditions	Yield of 10	Yield of 3	Ee ^b
1	(R)-6	CH2Cl2, without additive, rt, 1 d	91%	—	76%
2	(R)-8	CH2Cl2, without additive, rt, 1 d	95%	—	50%
3	(R)-8	CH2Cl2, mol. sieves (4Å), rt, 1 d	31%	37%	64%
4	(R)-6	11 (1 equiv), rt, 3 d	85%	8%	83%
5	(R)-6	Propanol (1 equiv), rt, 3 d	29%	25%	75%
6	(R)-8	Propanol (1 equiv), rt, 3 d	24%	25%	54%
7	(R)-6	CF3CH2OH (1 equiv), rt, 3 d ^c	25%	52%	79%
8	(R)-8	CF3CH2OH (1 equiv), rt, 3 d ^c	43%	15%	58%
9	(R)-6	12 (0.5 equiv), rt, 3 d	88%	2%	81%
10	(R)-8	12 (1 equiv), rt, 3 d ^d	34%	18%	39%
11	(R)-6	(S)-13 (0.1 equiv), rt, 3 d	42%	8%	94%
12	(R)-8	(S)-13 (0.1 equiv), rt, 3 d ^c	37%	5%	60%
13	(R)-8 ^e	(R)-BINOL (0.1 equiv), rt, 2 d	93%	—	80%
14	(R)-8	(R)-14 (0.1 equiv), rt, 4 d ^c	56%	14%	33%
15	(R)-6	(S)-13 (0.1 equiv), a) 0 °C, 10 h, b) rt, 2 d	63%	16%	94%

Molecular sieves are a simple and efficient additive for a variety of enantioselective carbon–carbon bond-forming reactions.^[4,30b] The application of finely powdered molecular sieves in the model aldol addition using (R)-8 as ligand afforded a lower yield of aldol products (31% of 10 and 37% of 3), although with a better enantioselectivity of 64% ee (compare entries 2 and 3). A high stereoselectivity (83% ee) and a good chemical yield were achieved when the aldol reaction was executed with ligand (R)-6 in the presence of 1 equivalent of the ionic liquid 11 as additive (see entry 4).^{[ 32 ]} Almost the same level of enantioselectivity and moderate to good yields of 10 and 3 could be attained by use of alcohols such as propanol or 2,2,2-trifluoroethanol (compare entries 1 with 5 and 7 as well as entries 2 with 6 and 8). The trifluoromethyl-substituted phenol 12 did not give a clear picture. The aldol reaction using the combination of (R)-6/12 (entry 9) gave a product with a slightly higher ee compared to the experiment without 12. However, when the aldol addition was carried by combination of 12 with (R)-8, the expected product was only formed with 39% ee (entry 10).

The self-assembly of several components, especially of two chiral ligands, into a highly active species is an attractive challenge in stereoselective synthesis.^{[ 29 ]} Therefore, we tested combinations of (R)-6 and (R)-8, respectively, with (R)-BINOL, steroidal BINOL-type ligand (R)-14,^{[ 33 ]} and prolinol derivative (S)-13 as chiral additives. Indeed, the combinations of (R)-6/(S)-13, (R)-8/(S)-13, and (R)-8/(R)-BINOL gave a significantly improved enantioselectivity (compare entries 1 and 11, entries 2 and 12, as well as entries 2 and 13). Not surprisingly, the combination of (R)-8/(R)-14 induced a dramatic drop of enantiomeric excess to 33% (see entries 2 and 14). A similar result (40% ee) was observed previously, where (R)-14 has been used as the only ligand in the aldol reaction of 1 and 2.^{[ 23 ]} Gratifyingly, an excellent level of stereoselectivity could be obtained by the ligand combination (R)-6 /(S)-13, starting the aldol reaction at 0 °C and then at room temperature, which clearly surpasses the uncombined ligand (R)-6 under the same reaction conditions (compare entry 10 in Table 1 and entry 15 in Table 2). Aldol reactions with aliphatic aldehydes (e.g., 2-phenylethanal and heptanal) using ligand (R)-6 under the reaction conditions as described in Table 1 provided the expected aldol products in high yields, but so far only with moderate enantioselectivity.

Desilylation of primary aldol product was easily performed by treatment of 10 with 2 N aqueous HCl solution at room temperature. The enantiomeric purities of the resulting desilylated aldol product were unambiguously established by ¹ H and ¹³C NMR spectroscopy of the MPTA ester prepared with (S)-configured Mosher's acid chloride.^{[ 34 ]} The assignment of the predominating configuration of the newly formed stereocenter of aldol product 10 as depicted in Eq. (2) is based on comparison of the specific optical rotation with the known unprotected compound. In accordance with Keck's, Mikami's, and our former results, the polymer-supported (R)-BINOL-titanium catalysts used herein promote the preferential attack of 2 to the Re face of the aldehyde investigated, resulting in the preferred formation of R-configured product 10.

In summary, the enantioselective aldol reaction of S-ketene silyl acetal 2 with aldehydes such as 1 using MPEG-supported BINOL-Ti(OiPr)₄ catalyst is possible. In this model reaction, the best results in terms of enantioselectivity were achieved with polymer-supported BINOL (R)-6-titanium catalyst in combination with the chiral additive (S)-13. The optimized reaction conditions described herein are the basis for the investigation of other aldehydes. Alternative applications of MPEG-supported BINOL derivatives for other carbon–carbon bond formations such as stereoselective allylations of carbonyl compounds are conceivable.

EXPERIMENTAL

General Methods

All reactions were performed under an argon atmosphere in flame-dried flasks, and the components were added by means of syringes. All solvents were dried by standard methods. IR spectra were measured with Beckman IR Acculab 4, Beckman IR 5A, Perkin-Elmer IR 1420, or Perkin-Elmer Fourier transform infrared (FT-IR) spectrometer Nicolet 5 SXC. Mass spectra (MS) spectra were recorded with a Varian MAT 711 spectrometer. ¹H and ¹³C NMR spectra were recorded on Bruker instruments (AC 500, WM 300, WH 270, AC 250) in CDCl₃ solution. The chemical shifts are given in relative to the tetramethylsilane (TMS) or to the CDCl₃ signal (δ _H = 7.27, δ _C = 77.0). Higher-order NMR spectra were approximately interpreted as first-order spectra if possible. Missing signals of minor isomers are hidden by signals of major isomers, or they could not be unambiguously because of low intensity. Neutral alumina (activity III, Fa. Merck) was used for column chromatography. Melting points (uncorrected) were measured with an apparatus from Büchi (SMP-20). Optical rotations were determined in a 1-mL cell with a path length of 10 cm using a Perkin-Elmer 241 polarimeter (Na_D line). The [α]_D values are given in 10⁻¹ deg cm²g⁻¹, and the concentrations are given in g/100 cm³.

Starting materials 1,^{[ 24 ]} 2,^{[ 35 ]} 5,^{[ 25 ]} (R)-4,^{[ 26 ]} and (R)-7 ^{[ 27 ]} were prepared by literature procedures. All other chemicals were commercially available and were used as received.

(R)-6-MPEGO-2,2′-dihydroxy-1,1′-binaphthalene ((R)-6)

A mixture of MPEG-polymer 5 (4.00 g, 0.79 mmol), 6-bromo-BINOL (R)-4 (0.565 g, 1.58 mmol), P(o-Tol)₃ (73 mg, 0.238 mmol), tributylamine (4.3 mL), and Pd(OAc)₂ (27 mg, 0.119 mmol) in dimethylformamide(DMF, 10 mL) was heated with vigorously stirring in an Ace flask at 130 °C for 18 h. The mixture was cooled to room temperature and poured in diethyl ether (500 mL), and the resulting precipitate was separate by filtration. Concentration of the filtrate and recrystallization (EtOH) of the crude product gave polymer-supported BINOL (R)-6 (3.77 g, 89%) as a colorless solid, mp 58–61 °C.

¹H NMR (250 MHz, CDCl₃): δ = 3.35 (s, 3 H, OMe), 3.45–3.85 (m, PEG), 4.32 (m, 2 H, PEG), 6.20 (br s, 2 H, OH), 6.43 (d, J = 17 Hz, 1 H, =CH), 7.06–7.09, 7.15–7.40, 7.76–7.85 (3 m, 2 H, 7 H, 2 H, =CH, Aryl), 7.90 (d, J = 9 Hz, 1 H, Aryl). [α]_D ²³ = −13.3 (c = 0.53, CHCl₃).

(R)-6-MPEGO-6′-bromo-2,2′-dihydroxy-1,1′-binaphthalene ((R)-8)

A mixture of MPEG-polymer 5 (2.50 g, 0.495 mmol), 6,6′-dibromo-BINOL (R)-7 (0.444 g, 1.00 mmol), P(o-Tol)₃ (46 mg, 0.15 mmol), tributylamine (2.7 mL), and Pd(OAc)₂ (17 mg, 0.075 mmol) in DMF (10 mL) was heated with vigorously stirring in an Ace flask at 130 °C for 18 h. The mixture was cooled to room temperature and poured in diethyl ether (400 mL), and the resulting precipitate was separated by filtration. Concentration of the filtrate and recrystallization (iPrOH) of the crude product gave polymer-bounded BINOL (R)-8 (2.15 g, 80%) as a colorless solid, mp 55 °C.

¹H NMR (250 MHz, CDCl₃): δ = 3.30 (s, 3 H, OMe), 3.45–3.88 (m, PEG), 4.28 (m, 2 H, PEG), 6.46 (br s, 2 H, OH), 6.47 (d, J = 18 Hz, 1 H, = CH), 6.90–7.40, 7.64–7.85 (2 m, 6 H, 4 H, = CH, Aryl), 7.90 (d, J = 9 Hz, 1 H, Aryl). [α]_D ²³ = − 41.8 (c = 0.55, CHCl₃).

Hydrogenolysis of Polymer-Supported Binol Derivative (R)-6

A suspension of anhyd. methanol (5 mL) and 10% Pd/C (50 mg) was saturated with H₂ for 0.5 h at room temperature. Then, the polymer derivative (R)-6 (400 mg, 0.075 mmol) was added, and the mixture was stirred under an H₂ atmosphere at normal pressure overnight at room temperature. The suspension was filtered through a sintered glass plug, which contained a pad of Celite eluting with methanol. The filtrate was concentrated in vacuo, and the residue was poured in diethyl ether (200 mL). After removal of the polymer by filtration, the resulting solution was concentrated, and the crude product was purified by recrystallization (iPrOH). Yield: 396 mg (99%) of (R)-9 as a colorless powder.

¹H NMR (250 MHz, CDCl₃): δ = 2.65, 2.95 (2 mc, 2 H each, CH₂), 3.35 (s, 3 H, OMe), 3.45–3.85 (m, PEG), 4.35 (m, 2 H, PEG), 6.25 (br s, 2 H, OH), 6.95–7.05, 7.10–7.40, 7.75–7.80 (3 m, 2 H, 6 H, 2 H, aryl), 7.85 (d, J = 9 Hz, 1 H, aryl).

Typical Procedure for Enantioselective Aldol Reaction Using Polymer-Supported (R)-BINOL-Derivative-Ti Catalysts

The polymer-supported titanium-(R)-BINOL-derivative catalyst was generated by a procedure described by Keck (method D).^{[ 28 ]} A mixture of Ti(OiPr)₄ and the polymer-supported BINOL-derivative in the solvent indicated in Table 1 (5 mL/mmol of aldehyde) was stirred for 1.5 h at rt. Aldehyde 1 (1.0 equiv) was added, and the mixture was stirred for an additional 10 min. Then a solution of S-ketene silyl acetal 2 (1.5 equiv) in the solvent indicated in Table 1 (5 mL/mmol of aldehyde) was added. The reaction mixture was stirred for the time and at the temperature according to the entries given in Tables 1 and 2. The reaction mixture was poured in diethyl ether (100 mL/mmol of aldehyde) and stirred for 30 min at rt.

Amounts of catalyst and additives, yields and enantioselectivities are given in Tables 1 and 2. For aldol reactions, using an additive (Table 2), the additive was added together with the BINOL-derivative. The resulting crude product was purified by column chromatography (neutral alumina, hexanes/EtOAc 3:1 or 4:1).

S-tert-Butyl 3-hydroxy-3-(2-styryl-oxazol-4-yl)propanethioate (3)^{[ 22 24 ]}

Colorless crystals, mp 105–107 °C, [α]_D ²³=+37.5 (c = 1.0, C₆H₆) (94% ee). ¹H NMR (CDCl₃, 250 MHz): δ = 7.55 (d, J = 1 Hz, 1 H, = CH), 7.55–7.30 (m, 6 H, = CH, Ph), 6.90 (d, J = 16.5 Hz, 1 H, = CH), 5.20 (dddd, J = 1, 4, 5, 8.5 Hz, 1 H, 3-H), 3.55 (d, J = 5 Hz, 1 H, OH), 3.05 (dd, J = 4, 16 Hz, 1 H, 2-H), 2.95 (d, J = 8.5, 16 Hz, 1 H, 2-H), 1.46 (s, 9 H, StBu). ¹³C NMR (CDCl₃, 75.5 MHz): δ = 199.2 (s, C-1), 161.6, 153.5 (2s, = CN, C = CH), 136.5, 135.3, 134.2, 129.1, 128.8, 127.2 (d, s, 4 d, 2 = CH, Ph), 113.6 (d, = CH), 64.3 (d, C-3), 50.0 (t, C-2), 48.5, 29.7 (s, q, tBu). MS (EI, 80 eV): m/z (%) = 331 (22) [M⁺], 274 (13) [M⁺ − tBu], 242 (47) [M⁺ − StBu], 200 (100) [M⁺ − CH₂COStBu].

S-tert-Butyl 3-(2-styryl-oxazol-4-yl)-3-(trimethylsiloxy)propanethioate (10)^{[ 22 ]}

Pale yellow crystals, mp 77–79 °C. ¹H NMR (CDCl₃, 250 MHz): δ = 7.55–7.30 (m, 7 H, 2 = CH, Ph), 6.89 (d, J = 16 Hz, 1 H, = CH), 5.24 (dd, J = 4.5, 8 Hz, 1 H, 3-H), 2.94 (dd, J = 4.5, 16 Hz, 1 H, 2-H), 2.88 (dd, J = 8, 16 Hz, 1 H, 2-H), 1.45 (s, 9 H, StBu), 0.21 (s, 9 H, SiMe₃). ¹³C NMR (CDCl₃, 62.9 MHz): δ = 197.3 (s, C-1), 161.5, 145.1 (2 s, = CN, C = CH), 136.2, 135.5, 134.3, 129.2, 128.9, 127.2 (d, s, 4 d, = CH, Ph), 113.9 (d, = CH), 65.5 (d, C-3), 52.1 (t, C-2), 48.1, 29.8 (s, q, tBu), 0.1 (q, SiMe₃).

Additional Information

For general procedure for desilylation of aldol product and transformation of the corresponding alcohol into the corresponding Mosher's ester, see Ref.^{[ 36 ]} The de value of the resulting ester was determined by ¹H and ¹³C NMR.

ACKNOWLEDGMENTS

We are most grateful for the generous support of this work by the Fonds der Chemischen Industrie. We thank Hülya Özbek and Sandra Schmidt for their experimental help and Dr. M. Schneider (Bayer Schering Pharma AG, Berlin) for the donation of compound (R)-14.

Notes

^a The ee was determined after the desilylation of 10.

^b Result taken from Ref. 22.

^c 60% of conversion.

^d 2 equivalents of BINOL ligand (R)-8 and 1 equivalent of Ti(OiPr)₄.

^a 10 mol% of the ligand was used.

^b The ee was determined after the desilylation of 10.

^c Ca. 80% of conversion.

^d Ca. 85% of conversion.

^e 15 mol% of the ligand was used.