(4R,5R)-4,5-Dicyclohexyl-2-ethyl-1,3,2-dioxaborolane1

[152428-72-3]  · C16H29BO2  · (264.21)

(representative starting material for asymmetric synthesis via a-halo boronic esters1,2)

Alternate Name: ethylboronic acid, (R,R)-1,2-dicyclohexyl-1,2-ethanediol ester; (R,R)-DICHED ethylboronate.

Physical Data: bp 85-87°C (100-200 Pa); 1H NMR d 0.78 (q, BCH2), 0.96 (t, CH3), 0.90-1.28 Hz and 1.50-1.77 (m, cyclohexyl), 3.82 (m, OCH).1

Preparative Methods: transesterification of B(O-i-Pr)3 with (R,R)-1,2-dicyclohexyl-1,2-ethanediol2 yields (4R,5R)-4,5-dicyclohexyl-2-isopropoxy-1,3,2-dioxaborolane, which reacts with ethylmagnesium chloride in THF at -78°C.1

Another simple route to (R,R)-1,2-dicyclohexyl-1,2-ethanediol [(R,R)-DICHED] ethylboronate (3) involves transesterification of dibutyl ethylboronate (1) with (R,R)-DICHED (2) (eq 1).1

The original preparation of 2 by hydrogenation of 1,2-diphenyl-1,2-ethanediol (4) over a rhodium on alumina catalyst2 has been substantially improved by in situ conversion of 4 to its methoxyborate ester (5) (eq 2), which allows the use of an active catalyst prepared in situ from rhodium chloride with ~2% reductive cleavage of the benzylic hydroxyl groups, a major side reaction if the free diol is hydrogenated.3

The hydrogenation is necessary because 4 is not a satisfactory chiral director.2,3 The large-scale preparation of 4 or its (S,S)-enantiomer from trans-stilbene is easily accomplished via Sharpless dihydroxylation.4 However, commercial samples of potassium osmate are sometimes less soluble than the batch used by Wang and Sharpless. The oxidation is fully reliable if the osmium compound is dissolved in water and added slowly to the reaction mixture.3

Ethylboronic esters such as 1 are readily accessible via the classical reaction of the ethyl Grignard reagent with a trialkoxyborane5 or the recent hydroboration of ethylene with boron trichloride and triethylsilane.6 However, an efficient and practical alternative is the direct ethylation of (R,R)-DICHED isopropoxyborate (6), prepared in situ from 2 and triisopropyl borate, with ethylmagnesium chloride (eq 3).1 It is important to prepare 6 that is free from hydroxylic contaminants and to ethylate it with a full equivalent of Grignard reagent in order to avoid the formation of by-product difficult to separate by distillation, most likely the B-O-B linked dimeric anhydride of DICHED borate.

A close analog of 3, (R,R)-DICHED methylboronate (8), has been made from commercially available trimethylboroxine and 1,2-diphenyl-1,2-ethanediol via the corresponding boronic ester (7) by hydrogenation over rhodium on alumina, prepared in situ from rhodium chloride (eq 4).3 This hydrogenation resulted in no detectable benzylic cleavage. In any attempt to adapt this approach to compounds of higher molecular weight, it should be taken into account that diphenylethanediol esters such as 7 can decompose, probably via pinacol rearrangement, if overheated during distillation.

Handling, Storage, and Precautions: (R,R)-DICHED ethylboronate (1) and similar boronic esters are generally stable during transfer and weighing in air, and do not hydrolyze. Their susceptibility to autoxidation appears comparable to that of common aldehydes, and storage in rigorously sealed containers is advised. No special hazards are known.

Applications

The major use of DICHED ethylboronate (3) and similar compounds is as starting material for highly stereoselective asymmetric synthesis. Actual isomer ratios obtained with 3 have never been measured accurately, but the closely related 1,2-diisopropyl-1,2-ethanediol propylboronate has been shown to furnish stereoselection >1000:1 after homologation with LiCHCl2 and substitution with methylmagnesium bromide.7 This very high ratio is the result of a sequential double diastereoselection. The wide range of synthetic applications possible with this homologation and substitution chemistry has been reviewed.8

The homologation process is illustrated by the conversion of the DICHED ethylboronate (3) to the corresponding 1-chloropropylboronate (10) via a borate complex (9) (eq 5). The structure of the borate complex and geometry of the metal cation catalysis of the rearrangement are supported by theoretical calculations.9 If zinc chloride is not added, the lithium ion from LiCHCl2 presumably functions in the same way, but reactions are slower and stereoselection is not as high.

Displacement of chloride from 10 by nucleophiles follows an analogous pathway, illustrated here by the reaction of lithium benzyl oxide with 10 to produce cation-coordinated borate 11, which rearranges to 12 (eq 6). Regardless of the mechanistic details, it is significant that the steric relationship of the alkyl substituent in intermediate 11 is similar to that of the chlorine atom that is not displaced in 9.

The 1-(benzyloxy)propyl boronic ester 12 was then used as an intermediate in the first synthesis of pure stegobinone, the pheromone of two anobiid beetle pests, the drugstore beetle and the furniture beetle. This pheromone is inactivated by small amounts of an epimer, and high stereopurity is therefore critical. Homologation of 12 with LiCHCl2 and the usual zinc chloride catalyst followed by methylation yielded boronic ester 13, which with LiCHCl2/ZnCl2 yielded chloro boronic ester 14 (eq 7).

Intermediate 14 served as a source of both halves of stegobinone. Oxidation of 14 with hydrogen peroxide yielded aldehyde 15 (eq 8) in 50-55% based on 3, diastereomeric purity >99%.1

Methylation of 14 yielded boronic ester 16, which was converted to ketone 17 in several steps (eq 9).1

Ketonic boronic ester 17 was converted to a boron enolate 18 with 9-BBN triflate and used in an aldol condensation with aldehyde 15 to produce the complete carbon skeleton of stegobinone (19) (eq 10). The steps not illustrated are standard organic transformations.

Stegobinone (19) epimerizes very easily at the enolizable asymmetric center, and the epimer is repellent to the insects. If the preparation does not supply very pure stegobinone initially, purification by standard methods is difficult. The boronic ester method is fairly lengthy but provides isomerically pure 19. A synthetic equivalent of intermediate aldehyde 15 might alternatively be made via aldol chemistry, though not necessarily more efficiently. The boronic ester route described here is especially useful for the highly stereocontrolled synthesis of the paired methyl substituents in intermediate 17.


1. Matteson, D. S.; Man, H.-W.; Ho, O. C., J. Am. Chem. Soc. 1996, 118, 4560.
2. Hoffmann, R. W.; Ditrich, K.; Köster, G., Stürmer, R., Chem. Ber. 1989, 122, 1783.
3. Hiscox, W. C.; Matteson, D. S., J. Org. Chem. 1996, 61, 8315.
4. Wang, Z.-M.; Sharpless, K. B., J. Org. Chem. 1994, 59, 8302.
5. Matteson, D. S. In The Chemistry of the Metal-Carbon Bond; Hartley, F.; Patai, S., Eds., John Wiley and Sons: Chichester, 1987, Vol. 4, p 307.
6. Matteson, D. S.; Soundararajan, R., Organometallics 1995, 14, 4157.
7. Tripathy, P. B.; Matteson, D. S., Synthesis 1990, 200.
8. (a) Matteson, D. S., Chem. Rev. 1989, 89, 1535. (b) Matteson, D. S., Tetrahedron 1998, 54, 10555. (c) Matteson, D. S., J. Organomet. Chem. 1999, 581, 51. (d) Matteson, D. S. Stereodirected Synthesis with Organoboranes; Springer Verlag: Berlin, 1995, 162.
9. Midland, M. M., J. Org. Chem. 1998, 63, 914.
10. Hoffmann, R. W.; Ladner, W.; Steinbach, K.; Massa, W.; Schmidt, R.; Snatzke, G., Chem. Ber. 1981, 114, 2786.

Donald S. Matteson

Washington State University, Pullman, WA, USA



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