Tetramethylammonium Triacetoxyborohydride

R4N(AcO)3BH
(R = Me)

[109704-53-2]  · C10H22BNO6  · Tetramethylammonium Triacetoxyborohydride  · (MW 263.14) (R = Bu)

[83722-99-0]  · C22H46BN06  · Tetramethylammonium Triacetoxyborohydride  · (MW 431.50)

(reducing agent for the regio- and stereoselective reduction of b-hydroxy ketones, amides, and oximino ethers)1

Alternate Name: TABH.

Physical Data: mp 96-98 °C.

Solubility: sol range of organic solvents including CH2Cl2, CHCl3, MeCN.

Form Supplied in: hygroscopic white powder; commercially available.

Preparative Methods: experimental procedures are available (eqs 1 and 2).5a,6

Purification: recrystallized from CH2Cl2-EtOAc.5a

Handling, Storage, and Precautions: moisture sensitive; irritant. Stable at 25 °C. Handle in a well ventilated fume hood.

Selective Reduction of Aldehydes.

Tetra-n-butylammonium triacetoxyborohydride (Bu4N(AcO)3BH) reduces aldehydes selectively in the presence of ketones (eq 3).2 b-Keto aldehydes are reduced to afford the corresponding 1,3-diol adduct; none of the derived primary b-hydroxy ketone is generated. It is proposed that the aldehyde carbonyl group is reduced first and the resulting hydroxyl group directs the delivery of hydride to the ketone site (eq 4).3

Similar observations have been reported with Sodium Triacetoxyborohydride.4 As shown in eq 5, reduction of a cyclic ketone containing a properly disposed hydroxyl function (for hydride delivery) proceeds to afford the derived equatorial alcohol with high diastereoselectivity. In contrast, an equal mixture of axial and equatorial alcohols are obtained when Sodium Borohydride is employed as the reducing agent.

Directed Reduction of b-Hydroxy Ketones.

Evans has reported that TABH may be employed to effect the stereoselective reduction of b-hydroxy ketones.5 Several reducing agents under a variety of conditions have been examined (eq 6 and Table 1). The reactivity and selectivity with TABH in AcOH/MeCN are superior to other solvent systems. The presence of HOAc is essential to reaction efficiency, as the protic acid catalyzes the rate determining association between the boron reagent and the resident substrate heteroatom.5b Acetonitrile is required since the reduction process may then be performed at lower temperatures without freezing of the reaction mixture; reduced temperatures are critical to obtaining high levels of stereoinduction.

As illustrated in the directed reductions shown in eqs 7 and 8, the level and sense of diastereoselectivity is independent of the local chirality within the substrate molecule.

Eqs 9 and 10 illustrate two additional important points with regard to the directed borohydride reduction: (1) the hydroxyl unit of an enol function may serve as the directing group (eq 9); (2) the stereoselective intramolecular hydride delivery may be relayed to effect generation of multiple stereogenic sites within an acyclic chain (eq 10).

Directed Reduction of Oximino Ethers.

Substrates with b-Hydroxy Substitution.

Stereocontrolled reduction of b-hydroxy oximino ethers has been reported by Williams.6 Eqs 11 and 12 indicate that whereas (E) substrates are reduced selectively, (Z) adducts react with TABH with inferior levels of stereoinduction. As illustrated in eqs 13-16, the stereochemical outcome of reduction of (E) oxime ethers is insensitive to the substrate local chirality, whereas the corresponding (Z) isomers afford b-hydroxy amines with high selectivity. However, in the latter instance the identity of the major isomer depends on the configuration of the a stereogenic center (eqs 13 and 14). Within the same context, with substrates containing a primary hydroxyl group, the a stereogenic center induces the preferred formation of the syn stereoisomer (eq 17). A mechanism-based understanding of the trends in stereoselectivity shown is not yet available.

Substrates with a-Hydroxy Substitution.

Reductions of a-hydroxy oximino ethers with TABH provide syn-1,2-hydroxyamines with high diastereoselectivity (eq 18).7 The observed stereochemical trend complements the previously observed anti selectivity achieved with Lithium Aluminum Hydride (LAH) or Diisobutylaluminum Hydride (DIBAL)8 as reducing agents, or when Pd-catalyzed stereoselective hydrogenation is employed.9 Unlike the case with b-alkoxy oximino ethers (eqs 11-17), neither the stereochemistry at the nitrogen (E vs. Z) nor that of the methyl group at the b-position has any effect on the stereochemical outcome of the reduction (e.g. eq 19).

Directed Reduction of Imides.

As shown in Table 2 and eq 20, imides may undergo directed selective reduction with TABH.10 The superior levels of stereochemistry obtained with the title borohydride, as opposed to LAH or Sodium Bis(2-methoxyethoxy)aluminum Hydride (Red-Al), may be attributed to the ability of TABH to undergo reduction through the directed pathway exclusively. It is noteworthy that upon protection of the hydroxyl group, no reaction is obtained with TABH. Reduction of the silyl ether with lithium Lithium Tri-s-butylborohydride (L-Selectride) proceeds with the opposite sense of stereochemical control.

Applications in Synthesis.

The ability of TABH and the corresponding sodium salt to participate in substrate-directed reductions with high levels of diastereoselection renders these reagents as attractive tools in the synthesis of complex molecules. For example, as illustrated in eq 21 in the synthesis of (-)-rocaglamide,11 the a-hydroxyl group strictly controls (>95%) the stereochemical outcome of the ketone reduction with TABH as the reducing agent. In contrast, hydrogenation (Palladium(II) Hydroxide as catalyst) of the same substrate affords only a 2:1 mixture of isomers. In the total synthesis of (+)-lepicidin A (eq 22), a highly selective b-hydroxy ketone reduction has been achieved (10:1).12 Stereoselective and directed reductions of b-hydroxy ketones have been employed in the synthesis of subunits of several medicinally important natural products, such as bryostatin I and II, in addition to mevinic acids, compactin, and mevinolin (eq 23, 93% yield, 13:1 selectivity).13


1. For general references on borohydrides, see (a) Reduction: Techniques and Applications in Organic Synthesis; Augustine, R. L., Ed.; Dekker: New York, 1968. (b) Hajos, A. Complex Hydrides and Related Reducing Agents in Organic Synthesis; Elsevier: New York, 1979. (c) Brown, H. C. Boranes in Organic Chemistry; Cornell UP: Ithaca, NY, 1972. (d) House, H. O. Modern Synthetic Reactions; Benjamin: Menlo Park, CA, 1972. (e) Greenwood, N. N. In Comprehensive Inorganic Chemistry; Bailer Jr., J. C.; Emeleus, H. J.; Nyholm, R.; Trotman-Dickenson, A. F., Eds.; Pergamon: Oxford, 1973; Vol. 1 pp 732-880. (f) Progress in Boron Chemistry; Steinberg, H.; McCloskey, A. L., Eds.; Pergamon: Oxford, 1964; Vol. 1. (g) Gerrard, W. The Organic Chemistry of Boron; Academic: New York, 1961. (h) Production of the Boranes and Related Research; Holzmann, R. T., Ed.; Academic: New York, 1967. (i) Lipscomb, W. N. Boron Hydrides; Benjamin: New York, 1963. (j) Boron Hydride Chemistry; Muetterties, E. L., Ed.; Academic: New York, 1975. (k) The Chemistry of Boron and Its Compounds; Muetterties, E. L., Ed.; Wiley: New York, 1967. (l) Stock, A. Hydrides of Boron and Silicon; Cornell UP: Ithaca, NY, 1933.
2. (a) Nutaitis, C. F.; Gribble, G. W. TL 1983, 24, 4287. (b) Gribble, G. W.; Nutaitis, C. F. OPP 1985, 17, 317.
3. For a comprehensive review of substrate-directable reactions, see: Hoveyda, A. H.; Evans, D. A.; Fu, G. C. CRV 1993, 93, 1307.
4. Saksena, A. K.; Mangiaracina, P. TL 1983, 24, 273.
5. (a) Evans, D. A.; Chapman, K. T. TL 1986, 27, 5939. (b) Evans, D. A.; Chapman, K. T.; Carreira, E. M. JACS 1988, 110, 3560. For general discussion, see: (c) Kim, B. M.; Sharpless, K. B. Chemtracts: Org. Chem. 1988, 1, 372. (d) Panek, J. S. Chemtracts: Org. Chem. 1992, 3, 188.
6. Williams, D. R.; Osterhout, M. H. JACS 1992, 114, 8750.
7. Williams, D. R.; Osterhout, M. H.; Reddy, J. P. TL 1993, 34, 3271.
8. Iida, H.; Yamazaki, N.; Kibayashi, C. CC 1987, 746.
9. Harada, K.; Shiono, S. BCJ 1984, 57, 1040.
10. Miller, S. A.; Chamberlin, A. R. JOC 1989, 54, 2502.
11. (a) Trost, B. M.; Greenspan, P. D.; Yang, B. V.; Saulnier, M. G. JACS 1990, 112, 9022. (b) Davey, A. E.; Schaeffer, M. J.; Taylor, R. J. K. JCS(P1) 1992, 2657.
12. Evans, D. A.; Black, W. C. JACS 1993, 115, 4497.
13. Evans, D. A.; Gauchet-Prunet, J. A.; Carriera, E. M.; Charette, A. B. JOC 1991, 56, 741.

Ahmad F. Houri & Amir H. Hoveyda

Boston College, Chestnut Hill, MA, USA



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