Diisopinocampheylboron Trifluoromethanesulfonate

(+)

[108266-89-3]  · C21H34BF3O3S  · Diisopinocampheylboron Trifluoromethanesulfonate  · (MW 434.36) (-)

[108161-70-2]

(enolboration reagent for enantio- and diastereoselective aldol condensation of oxazolines1 and ketones;2 also used for Ireland-Claisen rearrangement3)

Alternate Name: diisopinocampheylboron triflate; Ipc2BOTf.

Physical Data: colorless, viscous oil; bp <=150 °C/0.01 mmHg (bulb-to-bulb distillation); (-)Ipc2BOTf [a]D -43.5° (c = 30.4, hexane); 11B NMR (hexane) broad singlet at d = 60 ppm (with reference to BF3.OEt2).

Solubility: highly sol in both polar and nonpolar aprotic solvents, e.g. diethyl ether, THF, dichloromethane, pentane, hexane, etc.

Preparative Methods: the (+) enantiomer of the reagent (first reported in 1981)1 is prepared from commercially available (-)-a-pinene (~87% ee) by hydroboration with Borane-Dimethyl Sulfide in THF at 0 °C, which generates Diisopinocampheylborane, (+)-Ipc2BH, in more than 99% ee.4 The crystalline Ipc2BH is isolated and treated with Trifluoromethanesulfonic Acid at 0 °C either in dichloromethane5a or hexane.5b The reagent develops color in dichloromethane. However, it has been prepared in hexane as a clear and colorless solution which separates from an immiscible colored lower layer. In calculating the molarity of the reagent solution, a 60-70% conversion to triflate is assumed.2 The reagent is usually prepared in situ from Ipc2BH, and then its aldol reaction is carried out in the same flask by sequential addition of the required reagents5,11 (procedure A).6 Alternatively, the enantiomerically pure reagent can be conveniently prepared by treatment of commercially available (-)- or (+)-B-Chlorodiisopinocampheylborane (DIP-Cl™) with triflic acid at 0 °C in hexane (Scheme 1).7 This method (procedure B) generates Ipc2BOTf instantaneously in almost quantitative yield. The reagent generated by procedure B can be utilized for aldol reaction in the same manner as described for procedure A.

Handling, Storage, and Precautions: air sensitive; reacts instantaneously with protic solvents to liberate triflic acid; should be freshly prepared prior to use; the freshly prepared reagent turns from pale yellow to clear red upon standing. All transformations involving this reagent should be carried out under N2 using standard techniques for air sensitive reagents; use in a fume hood.

Boron Azaenolates from Oxazolines.

The reagent is useful for asymmetric aldol condensations of achiral oxazolines. Treatment of 2-ethyl-4-dimethyl-2-oxazoline with Ipc2BOTf in the presence of a tertiary amine furnishes a boron azaenolate. Without isolation, treatment with an aldehyde in ether at -78 °C provides an alkylated oxazoline, which is hydrolyzed and converted to b-hydroxy ester via treatment with Diazomethane. Although the yields for the four-step sequence are only moderate, the anti selectivities of the hydroxy acids are excellent with enantioselectivities of 77-85% ee (eq 1).1

Boron Enolates from Ketones.

Boron enolates are highly versatile intermediates in organic synthesis.8 Their high reactivity and stereoselectivity are often utilized for aldol condensation reactions.9,10 The reagent has been elegantly applied for regio- and stereoselective enolboration of ketones and subsequent enantio- and diastereoselective aldol reactions with aldehydes.11 For example, the aldol reaction between ethyl ketones and aldehydes using the (+) or (-) reagent in the presence of a tertiary amine in dichloromethane gives (via the desired (Z)-enolborinate) syn-a-methyl-b-hydroxy ketones in good enantiomeric excess (66-93% ee) and with high diastereoselectivity (&egt;95%) (eq 2). In contrast, the anti selectivity of the aldol product derived from diethyl ketone via formation of the (E)-enolate, derived from Ipc2BCl (DIP-Cl™) with Methacrolein, proceeds with negligible enantioselectivity.11a However, use of both the triflate and the chloride reagents in the aldol reaction of methyl ketones with aldehydes have been reported to give b-hydroxy ketones in moderate enantiomeric excess (53-78% ee) with a reversal in the enantioface selectivity of the aldehyde compared to the corresponding ethyl ketone syn-aldol. This variable selectivity is interpreted as evidence for the participation of competing chair and boat transition states.11

The aldol methodology mediated by Ipc2BOTf was successfully applied to a macrolide antibiotic synthesis. Paterson reported a convenient asymmetric synthesis of a C19-C27 segment of rifamycin S used in the Kishi synthesis, based on ethyl ketone aldol reactions mediated by optically pure reagent.12a He also reported the novel aldol approach to the synthesis of an enantiomerically pure C7-C15 segment of tirandamycin A.12b This was prepared via enolboration of the (R)-ethyl ketone by (-)-Ipc2BOTf in the presence of a tertiary amine. Addition of aldehyde to the corresponding enolborinate, followed by oxidative workup and chromatographic purification, led to the two separated syn-aldol isomers (8:1 ratio with 63% combined yield) with no anti-aldol product detected by HPLC. The major 1,2-syn-3,4-syn diastereomer is reported to be enantiomerically pure. Moreover, it was observed that enantiomeric excess of the major aldol isomer is significantly enhanced relative to the starting ketone. The corresponding aldol product is reduced to the 1,3-diol (eq 3) and subsequently converted to the enantiomerically pure C7-C15 segment of tirandamycin A via pyranone synthesis.12b

Dihydropyrones are valuable intermediates for the synthesis of a variety of substituted tetrahydropyran rings. Recently, stereoselective aldol reactions of b-chlorovinyl ketones using the dienol boronate derivative derived from chiral Ipc2BOTf was utilized for enantioselective formation of dihydropyrones. No detectable racemization was reported on the cyclization step (eq 4).12c

Ireland-Claisen Rearrangement.

Oh et al. recently reported the Ireland-Claisen rearrangement of a variety of O-protected 2-butenyl glycolates via chelated boron and tin triflates to give, after esterification, methyl 2-methoxy/benzyloxy-3-methyl-4-pentenoates.3 In reactions using Ipc2BOTf, diastereoselection as high as 99.5% was reported. The diastereoselection obtained in reactions using Tin(II) Trifluoromethanesulfonate, Zinc Trifluoromethanesulfonate, and Di-n-butylboryl Trifluoromethanesulfonate was far lower than in reactions with Ipc2BOTf. Moreover, the rate of rearrangement with boron enolates was found to be higher than the rates of rearrangement of the silyl ketene acetals or lithium enolate. As anticipated the cis-alkene gives better diastereoselectivity than the trans isomer (eq 5). With this high diastereoselection obtained using Ipc2BOTf, it is surprising that the enantioselectivity of this reaction is only 0-10% ee.3

Related Reagents.

(+)-B-Chlorodiisopinocampheylborane; Diisopinocampheylborane; (R,R)-2,5-Dimethylborolane.


1. (a) Meyers, A. I.; Yamamoto, Y. T 1984, 40, 2309. (b) JACS 1981, 103, 4278.
2. Paterson, I.; Goodman, J. M.; Lister, M. A.; Schumann, R. C.; McClure, C. K.; Norcross, R. D. T 1990, 46, 4663.
3. Oh, T.; Wrobel, Z.; Devine, P. N. SL 1992, 81.
4. (a) Brown, H. C.; Singaram, B. JOC 1984, 49, 945. (b) Brown, H. C.; Joshi, N. N. JOC 1988, 53, 4059.
5. (a) Paterson, I.; Lister, M. A.; McClure, C. K. TL 1986, 27, 4787. (b) Paterson, I.; Lister, M. A. TL 1988, 29, 585.
6. Purification of Ipc2BOTf by distillation is unnecessary and probably inadvisable as optimum results are obtained with freshly prepared undistilled reagent.2
7. Dhar, R. K.; Brown, H. C.; unpublished results.
8. (a) Kim, B. M.; Williams, S. F.; Masamune, S. COS 1991, 2, Chapter 5. (b) Evans, D. A. In Asymmetric Synthesis; Morrison, J. D.; Ed.; Academic: New York, 1984; Vol. 3, Chapter 1. (c) Heathcock, C. H. In Asymmetric Synthesis; Morrison, J. D.; Ed.; Academic: New York, 1984; Vol. 3, Chapter 2. (d) Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem. 1982, 13, 1.
9. For an examination of the effect of leaving group (X) on the stereoselective enolboration of ketones with various R2BX reagents (X = OTf, OMs, Cl, Br, I), see: (a) Brown, H. C.; Ganesan, K.; Dhar, R. K. JOC 1993, 58, 147. (b) Brown, H. C.; Dhar, R. K.; Bakshi, R. K.; Pandiarajan, P. K.; Singaram, B. JACS 1989, 111, 3441. (c) Goodman, J. M.; Paterson, I. TL 1992, 7223.
10. Selective trans deprotonation of the ketone-L2BOTf complex leads to formation of (Z)-enolborinate; see: Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R. JACS 1981, 103, 3099. An alternative explanation for L2BCl to (E)-enol borinate and L2BOTf to (Z)-enol borinate has been proposed by Corey and Kim; see: Corey, E. J.; Kim, S. S. JACS 1990, 112, 4976.
11. (a) Paterson, I.; Goodman, J. M. TL 1989, 30, 997. (b) Paterson, I.; Goodman, J. M.; Isaka, M. TL 1989, 30, 7121. (c) Paterson, I.; McClure, C. K. TL 1987, 28, 1229.
12. (a) Paterson, I.; McClure, C. K.; Schumann, R. C. TL 1989, 30, 1293. (b) Paterson, I.; Lister, M. A.; Ryan, G. R. TL 1991, 32, 1749. (c) Paterson, I.; Osborne, S. TL 1990, 31, 2213.

Raj K. Dhar

Aldrich Chemical Company, Sheboygan Falls, WI, USA



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