Diisopinocampheylborane

(+)

[21947-87-5]  · C20H35B  · Diisopinocampheylborane  · (MW 286.31) (-)

[21932-54-7]

(chiral hydroborating reagent for asymmetric hydroboration of cis-alkenes to provide access to optically active secondary alcohols;1 precursor for the preparation of a large number of chiral reagents for asymmetric synthesis.1)

Alternate Name: Ipc2BH.

Physical Data: white crystalline dimer.

Solubility: sparingly sol THF.

Analysis of Reagent Purity: active hydride is determined by hydrolysis of an aliquot and measuring the hydrogen evolved according to the standard procedure;2 enantiomeric purity is determined by measuring the rotation of the a-pinene liberated in its reaction with 0.5 equiv of N,N,N,N-Tetramethylethylenediamine (TMEDA)3 or reaction with aldehydes.4

Preparative Method: (+)-diisopinocampheylborane is prepared in high enantiomeric purity and good yield (Table 1) by hydroboration of commercially available (-)-a-pinene (of low enantiomeric purity) with Borane-Dimethyl Sulfide (BMS) complex, carried out by mixing the two reagents to make a solution of known molarity in THF at 0 °C or rt (eq 1); the mixture is left without stirring at 0 °C for ~12 h for the development of crystals (the slow crystallization facilitates the incorporation of the major diastereomer in the crystalline product, leaving the undesired isomer in solution); the supernatant solution is decanted using a double-ended needle; the crystalline lumps are broken and washed with diethyl ether and dried under vacuum (~12 mmHg) at rt.3,4

Handling, Storage, and Precautions: air sensitive, reacting instantaneously with protic solvents to liberate hydrogen; must be handled under an inert atmosphere (N2 or Ar); can be stored at 0 °C under inert atmosphere for several months without loss of hydride activity.4

Asymmetric Hydroboration.

Brown and Zweifel originally carried out the hydroboration of a-pinene to study the sensitivity of the a-pinene structure towards rearrangement. Surprisingly, the hydroboration reaction proceeded without rearrangement and stopped at the dialkylborane (R2BH) stage.5 This important reaction (reported in 1961) thus gave birth to a unique reagent, diisopinocampheylborane (Ipc2BH). The failure of this reagent to hydroborate a third molecule of a-pinene suggested the possibility of its application in asymmetric hydroboration of less sterically hindered alkenes.

The first substrate which was asymmetrically hydroborated using Ipc2BH was cis-2-butene, and the enantiomeric purity of the product 2-butanol (87% ee) obtained in this preliminary experiment was spectacular (eq 2), since Ipc2BH was made from a-pinene of low optical purity.5 This reaction represents the first nonenzymatic asymmetric synthesis for achieving high enantioselectivity. Its discovery marked the beginning of a new era of practical asymmetric synthesis obtained via reagent control.1,5

Later, Brown and co-workers developed the method described above for the preparation of enantiomerically pure Ipc2BH (>99% ee)3,4 and applied the reagent in the asymmetric hydroboration of prochiral alkenes. Oxidation of the trialkylboranes provided optically active alcohols. In the case of cis-alkenes, secondary alcohols were obtained in excellent enantiomeric purity (Figure 1). The reaction is general for most types of cis-alkene, e.g. cis-2-butene forms (R)-2-butanol in 98.4% ee, and cis-3-hexene is converted to (R)-3-hexanol in 93% ee. However, the reagent is somewhat limited in reactions with unsymmetrical alkenes; e.g. cis-4-methyl-2-pentene yields 4-methyl-2-pentanol with 96% regioselectivity but only 76% ee (Figure 1).6

Asymmetric hydroborations of heterocyclic alkenes are highly regio- and enantioselective. For example, hydroboration of 2,3-dihydrofuran with Ipc2BH followed by oxidation provides 3-hydroxyfuran in 83% ee, which can be upgraded to essentially the enantiomerically pure form (>99% ee) (Figure 2).7

Applications.

The ability of Ipc2BH to hydroborate cis-alkenes has been elegantly applied to the preparation of key intermediates which have been utilized in syntheses of valuable target molecules.1a For example, asymmetric hydroboration-oxidation of 5-methylcyclopentadiene to the corresponding optically active alcohol has been applied in the synthesis of loganin (eq 3).8a In another example, a prostaglandin precursor was obtained by the asymmetric hydroboration-oxidation reaction of methyl cyclopentadiene-5-acetate (eq 4).8b Ipc2BH has also been used in the preparation of PGF2a.9

Both the enantiomers of Ipc2BH have been elegantly applied in the asymmetric hydroboration of safranol isoprenyl methyl ether for the synthesis of carotenoids (3R,3R)-, (3S,3S)-, and (3R,3S;meso)-zeaxanthins (eq 5).10 (3S,5R,3S,5R)-Capsorubin, a carotenoid found in the red paprika Capsicum annuum, was synthesized via a key step involving asymmetric hydroboration of the unsaturated acetal followed by an aldol condensation (eq 6).11 Asymmetric hydroboration using Ipc2BH was also applied in the stereocontrolled synthesis of a linearly fused triquinane, (+)-hirsutic acid (eq 7).12

Diisopinocampheylborane is not an effective asymmetric hydroborating agent for 2-substituted 1-alkenes. High selectivities have, however, been achieved where one of the substituents is very bulky. This aspect has been elegantly demonstrated by the synthesis of both enantiomers of a precursor of tylonolide, the aglycone of tylosin, which is one of the members of the polyoxomacrolide antibiotics. In both cases the isomeric ratio was at least 50:1 (eqs 8 and 9).13

Application of Various Chiral Reagents Derived from Ipc2BH.

Diisopinocampheylborane does not normally yield satisfactory ee's in hydroboration reactions of 1,1-disubstituted alkenes, trans-alkenes, or trisubstituted alkenes. This problem has been partially solved by the introduction of Monoisopinocampheylborane, IpcBH2, which is derived from Ipc2BH. IpcBH2 handles trans-alkenes and trisubstituted alkenes effectively, since it is of lower steric requirement than Ipc2BH (Table 2). Moreover, IpcBH2 and Ipc2BH provide an entry into the synthesis of a large variety of optically active borinate and boronate esters. These esters have been successfully converted into a-chiral aldehydes, acids, amines, a-chiral cis- and trans-alkenes, a-chiral alkynes, b-chiral esters, ketones,1 etc.

Other reagents which have been derived from Ipc2BH include Diisopinocampheylboron Trifluoromethanesulfonate (Ipc2BOTf),14 B-Methoxydiisopinocampheylborane (Ipc2BOMe), and (+)-B-Chlorodiisopinocampheylborane and its bromo- and iodo analogs (Scheme 1).1 Ipc2BOTf and Ipc2BOMe reagents are used in stereoselective C-C bond forming reactions (aldol condensation and allylboration); Ipc2BCl (DIP-chloride™) is used for asymmetric reduction of prochiral ketones, and Ipc2BX(X = Br or I) for enantioselective opening of meso-epoxides to nonracemic halohydrins. Numerous applications of all these reagents have been reviewed in detail.1

Related Reagents.

(+)-B-Chlorodiisopinocampheylborane; Diisopinocampheylboron Trifluoromethanesulfonate; Dilongifolylborane; (R,R)-2,5-Dimethylborolane; B-Methoxydiisopinocampheylborane; Monoisopinocampheylborane.


1. For some excellent reviews on synthetic applications of diisopinocampheylborane and related reagents, see: (a) Brown, H. C.; Ramachandran, P. V. Advances in Asymmetric Synthesis; Hassner, A., Ed.; JAI Press: Greenwich, CT, 1994; Vol. 2, in press. (b) Brown, H. C.; Ramachandran, P. V. PAC 1991, 63, 307. (c) Brown, H. C.; Singaram, B. ACR 1988, 21, 287. (d) Srebnik, M.; Ramachandran, P. V. Aldrichim. Acta 1987, 20, 9. (e) Matteson, D. S. S 1986, 973.
2. Brown, H. C.; Kramer, G. W.; Levy, A. B.; Midland, M. M. Organic Synthesis via Boranes; Wiley: New York, 1975; p 239.
3. Brown, H. C.; Singaram, B. JOC 1984, 49, 945.
4. Brown, H. C.; Joshi, N. N. JOC 1988, 53, 4059.
5. Brown, H. C.; Zweifel, G. JACS 1961, 83, 486.
6. (a) Brown, H. C.; Desai, M. C.; Jadhav, P. K. JOC 1982, 47, 5065. (b) Brown, H. C.; Ayyangar, N. R.; Zweifel, G. JACS 1964, 86, 397.
7. Brown, H. C.; Prasad, J. V. N. V. JACS 1986, 108, 2049.
8. (a) Partridge, J. J.; Chadha, N. K.; Uskokovic, M. R. JACS 1973, 95, 532. (b) JACS 1973, 95, 7171.
9. Corey, E. J.; Noyori, R. TL 1970, 311.
10. Ruttimann, A.; Mayer, H. HCA 1980, 63, 1456.
11. Ruttimann, A.; Englert, G.; Mayer, H.; Moss, G. P.; Weedon, B. C. L. HCA 1983, 66, 1939.
12. Greene, A. E.; Luche, M.-J.; Serra, A. A. JOC 1985, 50, 3957.
13. Masamune, S.; Lu, L. D.-L.; Jackson, W. P.; Kaiho, T.; Toyoda, T. JACS 1982, 104, 5523.
14. Paterson, I.; Goodman, J. M.; Lister, M. A.; Schumann, R. C.; McClure, C. K.; Norcross, R. D. T 1990, 46, 4663.

Raj K. Dhar

Aldrich Chemical Company, Sheboygan Falls, WI, USA



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