[79547-82-3]  · C21H16O2  · (MW 300.36)

(reagent used as chiral proton source or chiral ligand in several enantioselective reactions)

Physical Data: mp 89-91 °C; [a]D27 +38.9 [c 0.68, THF, 99.3% ee (R)], [a]D28 -44.8 (c 1.4, CHCl3, 99.3% ee (R)]; HPLC [CHIRALCEL OD, 5% i-PrOH-hexane, retention time for the (R)-enantiomer, 25.12 min; for the (S)-enantiomer, 35.47 min]; IR (Nujol) 3478 cm-1; 1H NMR (300 MHz, CDCl3) d3.81 (s, 3H), 4.91 (s, 1H, exchangeable with D2O), 7.04 (br d, 1H, J = 7.7 Hz), 7.14-7.40 (m, 6H), 7.49 (d, 1H, J = 9.3 Hz), 7.86 (br d, 1H, J = 8.0 Hz), 7.90 (d, 2H, J = 8.5 Hz), 8.06 (d, 1H, J = 9.1 Hz); MS m/z = 300 (M+, 100%).

Solubility: soluble in alcohol, diethyl ether, toluene, and most organic solvents.

Form Supplied in: white solid.

Preparative Methods: (R)-2-hydroxy-2-methoxy-1,1-binaphthyl [(R)-BINOL-Me] can be prepared from commercially available (R)-1,1-bi-2-naphthol [(R)-BINOL] by the use of 1 mol equiv of methyl iodide and sodium hydride in N,N-dimethylformamide (DMF)1a or by the use of Mitsunobu reaction.1b

Purification: recrystallization from toluene-hexane or purification by silica gel column chromatography from a hexane- AcOEt (8:1) eluent.

Handling, Storage, and Precautions: very stable in air.

Enantioselective Protonation using SnCl4-BINOL Derivatives

Enantioselective protonation of silyl enol ethers is a very simple and attractive route for preparing optically active carbonyl compounds.2 However, it is difficult to achieve high enantioselectivity using simple chiral Brønsted acids because of the conformational flexibility in the neighborhood of the proton. In 1994, the authors found that the Lewis acid-assisted chiral Brønsted acid (LBA) is a highly effective chiral proton donor for enantioselective protonation.3a The coordination of a Lewis acid to a Brønsted acid restricts the direction of the proton and increases its acidity. In the presence of a stoichiometric amount of (R)-BINOL-SnCl4, the protonation of the trimethylsilyl enol ether derived from 2-phenylcyclohexanone proceeds in toluene at -78 °C to give the (S)-ketone with 97% ee. This reagent is applicable to various ketene bis(trialkylsilyl) acetals derived from a-arylcarboxylic acids. The observed absolute stereopreference can be understood in terms of the proposed transition state assembly. The trialkylsiloxy group is directed opposite to the binaphthyl moiety in order to avoid any steric interaction, and the aryl group stacks on this naphthyl group.

Taniguchi and Ogasawara have applied the enantioselective protonation using LBA to the asymmetrization of a meso-1,2-enediol bis(trimethylsilyl) ether having an endo-tricyclic []nonene framework (up to 90% ee) (1).3c The enantioselectivity has been increased from 9% ee (R = H) to 90% ee (R = i-Pr) by screening the (R)-substituent of (S)-2-alkoxy-2-hydroxy-1,1-binaphthyl [(S)-BINOL-R]. The chiral acyloin thus obtained can be transformed into two versatile chiral building blocks, (-)-ketodicyclopentadiene and (-)-ketotricyclononene, in optically pure forms via a sequence involving concurrent enzymatic acetylation and optical purification.

The authors have succeeded in the enantioselective protonation using a stoichiometric amount of an achiral proton source and a catalytic amount of (R)-BINOL-Me in place of (R)-BINOL (2).4 In the presence of 8 mol % of SnCl4, 10 mol % of (R)-BINOL-Me, and stoichiometric amounts of 2,6-dimethylphenol as an achiral proton source, protonation of the ketene bis(trimethylsilyl)acetal derived from 2-phenylpropanoic acid proceeds at -80 °C to give the (S)-carboxylic acid with 94% ee. (R)-BINOL-Me is far superior to (R)-BINOL as a chiral proton source during the catalytic protonation, and 2,6-dimethylphenol is the most effective achiral proton source. In addition, it is very important that the molar quantity of SnCl4 should be less than that of (R)-BINOL-Me to achieve a high enantioselectivity. For the reaction of 2-phenylcyclohexanone, however, the use of tin tetrachloride in molar quantities lower than BINOL-Me remarkably lowers the reactivity of the chiral LBA (3). Excess SnCl4 per chiral proton source, in contrast, promotes this protonation. In the protonation of silyl enol ethers less reactive than ketene bis(trialkylsilyl) acetals, chelation between excess tin tetrachloride and 2,6-dimethylphenol prevents the deactivation of the chiral LBA.

The mechanism of the catalytic cycle has been investigated by 1H NMR analysis of the 1 to 1 reaction mixtures of the silyl enol ether and chiral LBAs, (R)-BINOL-SnCl4 and (R)-BINOL-Me-SnCl4, at -78 °C. In the former case, two singlets for the TMS groups of Me3SiCl and the mono trimethylsilyl ether of (R)-BINOL have been observed at a molar ratio of 15 to 85. In the latter case, only one singlet for TMSCl has been observed. The presence of Me3SiCl suggests the generation of tin(IV) aryloxide intermediates. The catalytic cycle can be reasonably explained by assuming that the tin(IV) aryloxide intermediate is reconverted to the chiral LBA by receiving a proton and a chloride from 2,6-dimethylphenol and Me3SiCl or SnCl4, respectively (4).

The LBAs, BINOL-SnCl4 and BINOL-Me-SnCl4, are highly effective proton donors for the enantioselective protonation of allyltrimethyltins to give optically active olefins.3d In the presence of 1.5 equiv of (R)-BINOL-Me-SnCl4 in toluene, the protonation of (E)-3-phenyl-2-butenyltrimethyltin proceeds rapidly at -78 °C to form (S)-3-phenylbut-1-ene with good enantioselectivity and complete g-regioselectivity (5). The enantioselectivity is increased by lowering the reaction temperature to -90 °C in dichloromethane, and is dramatically decreased by using sterically bulky tin substituents. This latter tendency is interesting in that the enantioselectivity is independent of the steric features of the trialkylsilyl substituents in the protonation of silyl enol ethers with LBA. In the above protonation, a proton of (R)-LBA approaches the si-face of the g-olefinic carbon of (E)-3-phenyl-2-butenyltrialkyltin, while it approaches the opposite enantioface in the protonation of the analogous ketene bis(trimethylsilyl) acetal derived from 2-phenylpropionic acid.3a In contrast, the enantioselectivity for the protonation of 1-(trimethylstannyl)methyl-2-phenylcyclohexene as a (Z)-allyltrimethyltin is moderate, and the absolute stereochemical selectivity is analogous to that in the protonation of silyl enol ethers derived from 2-phenylcyclohexanone (6).

The E/Z substrate-dependent absolute stereochemistry and the steric influence of tin-substituents on the enantioselectivity observed in these reactions suggest that the mechanism is essentially different from that of silyl enol ethers. Although the detailed stereochemical course is not ascertained, it is possible that the protonation may occur via a two chlorine-bridged intermediate involving allyltrimethyltin and LBA.

Stereoselective Isomerization Catalyzed SnCl4-biphenol Derivatives

Protodesilylation and isomerization are able to occur during the reaction of silyl enol ethers with a Brønsted acid. The thermodynamic equilibration of trimethylsilyl enol ethers catalyzed by a Brønsted acid was first reported by Stork and Hudrlik in 1968.5 However, this equilibration was not established as a synthetically useful procedure, since the use of a Brønsted acid was seriously complicated by the concurrent formation of higher-molecular-weight materials and ketones. The greater stability of the Si-O bond in silyl enol ethers and the milder nucleophilicity of the conjugate base to the silicon atom favor the latter process. The authors have found that the regio and stereoselective isomerization of a kinetic silyl enol ether to a thermodynamic one is catalyzed by LBA.6 Kinetic TBDMS enol ethers are isomerized to the thermodynamic ones in the presence of catalytic amounts of the coordinate complexes of tin tetrachloride and the monoalkyl ethers of BINOL or biphenol (BIPOL). On the other hand, use of the coordinate complexes with biphenol and other monoaryl alcohols affords predominantly the corresponding ketones. For the various structurally diverse substrates, the isomerization cleanly proceeds in the presence of 5 mol % of the achiral LBA, BIPOL-i-Pr-SnCl4. The catalyst is effective not only for cyclic silyl enol ethers but also acyclic ones, and Z-isomers are stereoselectively produced (7).

A one-pot procedure from the racemic silyl enol ether to (S)-2-phenylcyclohexanone has been realized by combination of the isomerization and subsequent enantioselective protonation catalyzed by (R)-BINOL-Me in the presence of 2,6-dimethylphenol, tin tetrachloride, and TMSCl (8). Furthermore, the authors have succeeded in the enantiomer-selective isomerization of racemic silyl enol ethers. For example, during the isomerization of the same racemic silyl enol ether with 5 mol% of (R)-BINOL-Me- SnCl4 at -78 °C for 2 min, the (R)-silyl enol ether is recovered in 42% yield with 97% ee. This absolute stereopreference is consistent with that in the above enantioselective protonation (9).

Enantioselective Polyene Cyclization Catalyzed SnCl4- BINOL Derivatives

Non-enzymatic enantioselective polyene cyclizations are very attractive alternatives to the multistep synthesis from naturally occurring chiral synthons. The authors have succeeded in the first enantioselective biomimetic cyclization of polyprenoids catalyzed by LBA.7 (-)-Ambrox® is the most important commercial substitute for ambergris, due to its unique olfactory and fixative properties. The successful preparation of (-)-ambrox® has been achieved by the enantioselective cyclization of homofarnesol promoted by (R)-BINOL-Me-SnCl4, although the enantioselectivity and diastereoselectivity is moderate (10).

Cyclization of the more reactive o-geranylphenol with (R)-BINOL-SnCl4 gives the trans-fused tricyclic compound as a major diastereomer (36% ee, 84% ds) in good yield (11). The enantioselectivity is improved to 50% ee by using (R)-BINOL-Me-SnCl4. The monobenzoyl ester of (R)-BINOL [(R)-BINOL-Bz]-SnCl4 complex is the most effective for controlling the absolute and relative stereochemistries (54% ee, 95% ds).

The authors have found that the same tricyclic ether is obtained with much better selectivity from geranyl phenyl ether (12). Surprisingly, the reaction proceeded smoothly even in the presence of 20 mol % of this LBA to give the desired compound with 77% ee and 98% ds. This reaction is surmised to take place via a [1,3]-rearrangement and subsequent cyclization, although this has not yet been confirmed.

(-)-Chromazonarol, a minor constituent of the brown Pacific seaweed, has been synthesized using LBA-promoted enantioselective cyclization. The cyclization of 4-benzyloxyphenyl farnesyl ether with (S)-LBA gives the desired tetracyclic compound as the major diastereomer in 44% ee (13).

This approach using LBA has been applied to the enantioselective cyclization of homo(polyprenyl)arenes possessing an aryl group that serves as a less-nucleophilic terminator than a hydroxy group.8 The reaction of 1-homogeranyl-4-(tert-butyldiphenylsiloxy)benzene with (R)-BINOL-Me-SnCl4 gives the desired tricyclic compound in 13% yield with 72% ee. The other products are monocyclization products. The enantioselectivity of the tricyclic compound is improved to 81% ee when mono(o-fluorobenzyl) ether of (R)-BINOL [(R)-BINOL-o-F-Bn] is used instead of BINOL-Me. The desilylation and subsequent diastereoselective cyclization of a crude mixture, which is obtained in the above enantioselective cyclization, gives the desired tricyclic compound in 78% ee and 94% yield in three steps. This compound can be converted to (+)-ferruginol (14).

The enantioselective cyclization of 1-homogeranyl-3-(tert- butyldiphenylsiloxy)benzene with use of (R)-BINOL-o-F-Bn gives trans-fused tricyclic compound in 78% ee (trans only), together with the monocyclization products. The subsequent diastereoselective cyclization with BF3·Et2O gives (+)-13-acetoxypodocarpa-8(14)-en-13-one, a versatile intermediate for synthesis of naturally occurring diterpenes.

Tetracyclic terpene from Eocene Messel shale (Germany) can be also synthesized by using the LBA-induced enantioselective cyclization of 3-homofarnesyltoluene as a key step (16).

Direct Catalytic Enantioselective Aldol Reactions

Yamada and Shibasaki have found that a direct catalytic enantioselective aldol reaction of an aldehyde and unmodified ketone is promoted by a chiral barium complex (5 mol %) prepared from Ba(O-i-Pr)2 and 2.5 mol equiv of (R)-BINOL-Me.9 The possible structure of the barium catalyst which plays the role of a Lewis acid and a Brønsted base, has been characterized by LDI-TOFMS, 13C-NMR spectroscopy and extensive studies of reaction conditions (17).

Enantioselective Intramolecular Cyclization (SN2 reaction)

The desymmetric transformation of meso-structures has been recognized as a versatile synthetic method for optically active compounds in organic enzymatic processes. The enantioselective intramolecular cyclization of the bis-phenyllithium species, which is generated by addition of butyllithium to a solution of cis-3,5-di(bromophenoxy)cyclopentene, has been attained by addition of lithium salt (1.2 equiv) of (R)-BINOL-Me to produce a cyclopenta[b]benzofuran with 87% ee (18).10

Related Reagents.

(R)-2-Isoporpoxy-2-hydroxy-1,1-binaphthyl; 2-isopropoxy-2-hydroxy-1,1-biphenyl; (R)-2-o-fluorobenzyloxy-2-hydroxy-1,1-binaphthyl; (R)-2-benzoxy-2-hydroxy-1,1-binaphthyl.

1. (a) Tamai, Y.; Qian, P.; Matsunag, K.; Miyano, S., Bull. Chem. Soc. Jpn. 1992, 65, 817. (b) Takahashi, M.; Ogasawara, K., Tetrahedron: Asymmetry 1997, 8, 3125.
2. Fehr, C., Angew. Chem. Int. Ed. Engl. 1996, 35, 2566.
3. (a) Ishihara, K.; Kaneeda, M.; Yamamoto, H., J. Am. Chem. Soc. 1994, 116, 11179. (b) Ishihara, K.; Nakamura, S.; Yamamoto, H., Croat. Chem. Acta 1996, 69, 513. (c) Taniguchi, T.; Ogasawara, K., Tetrahedron Lett. 1997, 38, 6429. (d) Ishihara, K.; Ishida, Y.; Nakamura S.; Yamamoto, H., Synlett 1997, 758.
4. (a) Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H., J. Am. Chem. Soc. 1996, 118, 12854. (b) Yanagisawa, A.; Ishihara, K.; Yamamoto, H., Synlett 1997, 411.
5. (a) Stork, G.; Hudrlik, P. F., J. Am. Chem. Soc. 1968, 90, 4462. (b) House, H. O.; Czuba, L. J.; Gall, M.; Olmstead, H. D., J. Org. Chem. 1969, 34, 2324.
6. Ishihara, K.; Nakamura, H.; Nakamura, S.; Yamamoto, H., J. Org. Chem. 1998, 63, 6444.
7. Ishihara, K.; Nakamura, S.; Yamamoto, H., J. Am. Chem. Soc. 1999, 121, 4907.
8. Ishihara, K.; Ishibashi, H.; Yamamoto, H., J. Am. Chem. Soc. 2001, 123, 1505.
9. Yamada, Y. M. A.; Shibasaki, M., Tetrahedron Lett. 1998, 39, 5561.
10. Nishiyama, H.; Sakata, N.; Motoyama, Y.; Wakita, H.; Nagase, H., Synlett 1997, 1147.

Kazuaki Ishihara & Hisashi Yamamoto

Nagoya University Furo-cho, Chikusa, Nagoya, Japan

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.