Tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole1

(S)

[112022-81-8]  · C18H20BNO  · Tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole  · (MW 277.20) (.BH3)

[112022-90-9] (R)

[112022-83-0]

(one of many chiral oxazaborolidines/chiral Lewis acids useful as enantioselective catalysts for the reduction of prochiral ketones,1-3 imines,4 and oximes,2e,f,5 and the reduction of 2-pyranones to afford chiral biaryls;6 other chiral oxazaborolidines have been used for the addition of diethylzinc to aldehydes,7 asymmetric hydroboration,8a,b the Diels-Alder reaction,9-11 and the aldol reaction12,13)

Physical Data: mp 79-81 °C.

Solubility: very sol THF, CH2Cl2, toluene.

Preparative Methods: see text.

Purification: Kugelrohr distillation (50 °C/0.001 mbar)

Handling, Storage, and Precautions: the free oxazaborolidine must be rigorously protected from exposure to moisture. The crystalline borane complex is more stable, and is the preferred form to handle and store this catalyst.

Enantioselective Ketone Reduction.

The major application of chiral oxazaborolidines has been the stoichiometric (as the oxazaborolidine-borane complex) (eq 1) and catalytic (in the presence of a stoichiometric borane source) (eq 2) enantioselective reduction of prochiral ketones.1 These asymmetric catalysts work best for the reduction of aryl alkyl ketones, often providing very high (>95% ee) levels of enantioselectivity.

Following from the work of Itsuno2 and Corey,3 over 75 chiral oxazaborolidine catalysts have been reported for the reduction of prochiral ketones [(1),2,3a,14,15a,e,f,16d-f,17b (2),16d,18b (3),3,6,19b-e,20,21,26c (4),16a (5),1b,16c,22 (6),22b (7),3d,18a (8),16b (9),23 (10),24 (11),24 (12),19a]. Oxazaborolidines derived from proline (3) (see a,a-Diphenyl-2-pyrrolidinemethanol) and valine (1; R4 = i-Pr) (see 2-Amino-3-methyl-1,1-diphenyl-1-butanol) have received the most attention.

Unsubstituted (B-H) oxazaborolidines (16) are prepared from a chiral b-amino alcohol (13) and a source of borane (Diborane, Borane-Tetrahydrofuran, Borane-Dimethyl Sulfide, or H3B.NMe3) via a multistep process (eq 3). Formation of the initial amine-borane complex (14) is generally exothermic, and this intermediate can often be isolated. Gentle heating with the loss of one mole of hydrogen results in the formation of (15). Continued heating with the loss of a second mole of hydrogen then affords oxazaborolidine (16). When R4 and R5 are connected, forming a four- or five-membered ring, more forcing conditions (70-75 °C, 1.7 bar, 48-72 h) are required to effect this conversion due to the additional ring strain. [Caution: under these conditions, borane or diborane in the vapor phase can begin to decompose.25] Finally, additional borane is added to afford the oxazaborolidine-borane complex (17).

Free oxazaborolidine (16), by itself, will not reduce ketones. Furthermore, (16) is not particularly stable, reacting with moisture (H2O), air (O2), unreacted amino alcohol, other alcohols,8c or, depending on the substituents, with itself to form various dimers.3a,8c,d,15d,26,27a This instability is due to the strain of a partial double bond between nitrogen and boron (eq 4). Formation of the oxazaborolidine-borane complex (17) tends to release some of this strain. As such, (16) and (17) are generally prepared and used in situ without isolation; in many cases, they have not been fully characterized.17c

Oxazaborolidines substituted at boron (1; R1 = alkyl, aryl) are prepared from a chiral b-amino alcohol and the corresponding boronic acid in a two-step process (eq 5).3b,9 Heat and an efficient method of water removal (i.e. azeotropic distillation, molecular sieves) are required to drive the second step. When R4 and R5 are connected, more forcing conditions are necessary, both to complete the second step and to prevent the intermediate from proceeding to an alternate disproportionation product.21 Alternative procedures using bis(diethylamino)phenylborane (eq 6),26a,b trisubstituted boroxines (eq 7),21,27 and ethyl or butyl bis(trifluoroethyl)boronate esters (eq 8)19e have been developed to circumvent these problems. The substituted oxazaborolidines are more stable than unsubstituted (B-H) oxazaborolidines (i.e. they can be handled in the presence of air, and do not form dimers), but are still prone to decomposition by moisture (H2O).21 In many cases the substituted oxazaborolidines have been isolated, purified, and characterized.

Substituted oxazaborolidines also react with borane (B2H6, H3B.THF, or H3B.SMe2) to form an oxazaborolidine-borane complex (19) (eq 9).3b,27 The oxazaborolidine-borane complex, by releasing the strain of the partial double bond between the ring boron and nitrogen, is more stable than the free oxazaborolidine, and in many cases exists as a stable crystalline solid.21c,27,28

The oxazaborolidine-borane complex (19) can be used stoichiometrically (eq 1) or catalytically (eq 10) for the enantioselective reduction of prochiral ketones.27a When used catalytically, the oxazaborolidine-borane complex (19) is the second intermediate in the catalytic cycle (eq 10) proposed to explain the behavior of the oxazaborolidine catalyst.3a,29 Subsequent coordination between the Lewis acidic ring boron and the carbonyl oxygen activates the ketone toward reduction. Intramolecular hydride transfer from the BH3 coordinated to the ring nitrogen then occurs via a six-membered ring chair transition state.17b,27a,30 Following hydride transfer, the alkoxy-BH2 dissociates, and oxazaborolidine (1) is free to begin the cycle again. The diastereomeric transition state model (20), leading to the enantiomeric carbinol product, is disfavored due to unfavorable 1,3-diaxial steric interactions between RL and R1. Additional work will be required to better understand the catalytic cycle and the intermediates involved to further improve the oxazaborolidine catalysts. The behavior of the catalysts has been the subject of molecular orbital calculations in a series of 12 papers.31 It should be noted, however, that not all of the results and conclusions are supported by experimental observations.

The enantioselectivities reported for the reduction of acetophenone and 1-tetralone using several representative chiral (4S)-oxazaborolidine catalysts are summarized in Table 1. The oxazaborolidines derived from (S)-azetidinecarboxylic acid and (S)-proline provide the best results. It is interesting to note the reversal in enantioselectivity going from catalyst (5a) to (6a).

Oxazaborolidine catalyzed reductions are generally performed in an aprotic solvent, such as dichloromethane, THF, or toluene. When the reactions are run in a Lewis basic solvent, such as THF, the solvent competes with the oxazaborolidine to complex with the borane, which can have an effect on the enantioselectivity and/or rate of the reaction.27a The solubility of the oxazaborolidine-borane complex can be the limiting factor for reactions run in toluene, although this problem has been circumvented by using oxazaborolidines with more lipophilic substituents (R1 = n-Bu; R2, R3 = 2-naphthyl).19b-d We have found dichloromethane to be the best overall solvent for these reactions.27a

The reactions are typically performed using H3B.THF, H3B.SMe2, or Catecholborane19d as the hydride source. When using H3B.THF or H3B.SMe2, two of the three hydrides are effectively utilized.27a This is only true for reactions run at temperatures greater than -40 °C. At lower temperatures, only one hydride is transferred at a reasonable rate. When two hydrides are used, there is some evidence that the enantioselectivity for transfer of the second hydride is different, and may in fact be lower.27a Whether this implies that an alternative catalytic cycle operates, whereby the alkoxy-BH2 intermediate generated during the first hydride transfer remains coordinated to the oxazaborolidine, and then transfers the second hydride (with a different degree of enantioselectivity), or that some other intermediate present is active, but not as an enantioselective reducing agent, will require further investigation. In any event, the amount of BH3 used should be at least 0.5 mole per mole of ketone plus an amount equal to the oxazaborolidine catalyst, with the possibility that 1 mole per mole provides slightly higher enantioselectivity. When catecholborane is used as the hydride source, a 50-100% excess of this reagent is used.

The mode of addition and the reaction temperature both affect the enantioselectivity of the reaction. The best results are obtained when the ketone is added slowly to a solution of the oxazaborolidine (or oxazaborolidine-borane complex) and the borane source, at as low a temperature that provides a reasonable reaction rate.27a This is in contrast to a previous report that indicated that oxazaborolidine-catalyzed reductions lose stereoselectivity at lower temperatures.19d With unsubstituted (R1 = H) oxazaborolidines, higher temperatures may be required due to incomplete formation of the catalyst, the presence of dimers, and/or other intermediates.26c

In their role as enantioselective catalysts for the reduction of prochiral ketones, chiral oxazaborolidines have been used for the preparation of prostaglandins,3a PAF antagonists,3a a key intermediate of ginkgolide B,32a bilobalide,32b a key intermediate of forskolin,32c (R)- and (S)-fluoxetine,32d (R)- and (S)-isopreterenol,19c vitamin D analogs,33 the carbonic anhydrase inhibitor MK-0417,21b the dopamine D1 agonist A-77636,20b taxol,34 the LTD4 antagonists L-695,499 and L-699,392,35 the b-adrenergic agonist CL 316,243,36 and the antiarrhythmic MK-0499.37 They have also been used for the synthesis of chiral amines,38,39 a-hydroxy acids,19d,40a benzylic thiols,40c the enantioselective reduction of trihalomethyl ketones,40a,b,d and ketones containing various heteroatoms.17a,21b,27a,35,37

Enantioselective Reduction of Imines and Ketoxime O-Ethers.

In addition to the reduction of prochiral ketones, chiral oxazaborolidines have been employed as enantioselective reagents and catalysts for the reduction of imines (eq 11)4,23 and ketoxime O-ethers (eq 12)2e,f,5 to give chiral amines. It is interesting to note that the enantioselectivity for the reduction of ketoxime O-ethers is opposite that of ketones and imines. For more information, see 2-Amino-3-methyl-1,1-diphenyl-1-butanol.

Enantioselective Addition of Diethylzinc to Aldehydes.

Oxazaborolidines derived from ephedrine have been used to catalyze the addition of Diethylzinc to aldehydes (eq 13).7 Both the rate and enantioselectivity are optimized when R1 = H. Aromatic aldehydes generally react faster than aliphatic aldehydes, and the enantioselectivity for aromatic aldehydes is good to excellent (86-96% ee).

Other Applications.

Chiral oxazaborolidines derived from ephedrine have also been used in asymmetric hydroborations,8a,b and as reagents to determine the enantiomeric purity of secondary alcohols.8c Chiral 1,3,2-oxazaborolidin-5-ones derived from amino acids have been used as asymmetric catalysts for the Diels-Alder reaction,9-11 and the aldol reaction.12,13

Related Reagents.

2-Amino-3-methyl-1,1-diphenyl-1-butanol; a,a-Diphenyl-2-pyrrolidinemethanol; Ephedrine-borane; Norephedrine-Borane.


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David J. Mathre & Ichiro Shinkai

Merck Research Laboratories, Rahway, NJ, USA



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