Chiral alcohols hydroboration

Another possibility for asymmetric reduction is the use of chiral complex hydrides derived from LiAlH. and chiral alcohols, e.g. N-methylephedrine (I. Jacquet, 1974), or 1,4-bis(dimethylamino)butanediol (D. Seebach, 1974). But stereoselectivities are mostly below 50%. At the present time attempts to form chiral alcohols from ketones are less successful than the asymmetric reduction of C = C double bonds via hydroboration or hydrogenation with Wilkinson type catalysts (G. Zweifel, 1963 H.B. Kagan, 1978 see p. 102f.). 

An extensive array of chiral phosphine ligands has been tested for the asymmetric rhodium-catalyzed hydroboration of aryl-substituted alkenes. It is well known that cationic Rh complexes bearing chelating phosphine ligands (e.g., dppf) result in Markovnikoff addition of HBcat to vinylarenes to afford branched boryl compounds. These can then be oxidized through to the corresponding chiral alcohol (11) (Equation (5)) ... 

The Focus On box on page 433 described a hydroboration reaction that produces a single enantiomer of a chiral alcohol as the product. The chirality of one enantiomer of the boron hydride reagent is used to control the formation of a single enantiomer of the product. As discussed in that Focus On box, the drawback to this reaction is that it requires one mole of the chiral borane for each mole of chiral alcohol that is produced. The chiral reagent is rather expensive because it must be resolved or prepared from another enantiomerically pure compound. A more desirable process would use the expensive chiral reagent as a catalyst so that a much smaller amount could be employed to produce a larger amount of the chiral product. 

In reactions with polymer-bound catalysts, a mass-transfer limitation often results in slowing down the rate of the reaction. To avoid this disadvantage, homogenous organic-soluble polymers have been utilized as catalyst supports. Oxazaborolidine 5, supported on linear polystyrene, was used as a soluble immobilized catalyst for the hydroboration of aromatic ketones in THF to afford chiral alcohols with an ee of up to 99% [40]. The catalyst was separated from the products with a nanofiltration membrane and then was used repeatedly. The total turnover number of the catalyst reached as high as 560. An intramolecularly cross-linked polymer molecule (microgel) was also applicable as a soluble support [41]. 

Reviews on the synthesis of chiral alcohols by asymmetric hydroboration of prostereogenic alkenes have been published47-53 and this topic is also covered in Houben-Weyl, Vol. 6/la, pp 494-553. The synthesis of asymmetric hydroborating agents, and their reactivity and enan-tioselectivity in reactions with major classes of prostereogenic alkenes, is also described in Sections D.2.5.2.1.2. and D.2.5.2.1.3. 

A very important feature of the monoalkylmonoisopinocampheyl boranes obtained from prostereogenic alkenes is their tendency to crystallize from the reaction mixture. This crystallization process is an efficient resolution technique providing crystalline material of high optical purity. Utilizing this technique, chiral alcohols of essentially 100% ee can be prepared by the hydroboration of prostereogenic, A -disubstituted and trisubstituted alkenes with monoisopinocampheylborane71, 73. 

Table 3. Selected Chiral Alcohols via Catalytic Asymmetric Hydroboration/Oxidation of Alkenes with 1,3,2-Benzodioxaborole...

Brown and coworkers have described an alternative synthesis of chiral alkylboronic esters. In this synthesis prochiral alkenes are hydroborated with monoisopinocamphenylborane to yield isopinocam-phenylalkylboranes which are then readily transformed to chiral alkyllraronic esters (Scheme 39). Homologation with dichloromethyllithium, followed by reduction with potassium triisopropoxyborohy-dride (KIPBH) and oxidation, finely yields B-chiral alcohols (Scheme 40). These alcohols are not easily prepared by other methods. Aldehydes can be prepared by homologation from chiral alkylboronic esters with LiCH(OMe)SPh and oxidation (Scheme 41). ... 

Alkyl-l,3,2-dioxaborinanes, prepared by asymmetric hydroboration of prostereogenic olefins with monoisopinocampheylborane and subsequent removal of the chiral auxiliary, react with methoxy(phenylthio)methyllithium followed by treatment with mercuric(II) chloride, to give a-methoxyalkyl derivatives. Oxidation of these intermediates in a pH 8 phosphate buffer provides x-chiral aldehydes (method ) which are transformed by further oxidation into the corresponding a-chiral acids (method ) and by reduction into /i-chiral alcohols (method )14. 

Chiral alcohols, which are difficult to prepare in high optical purity by asymmetric hydroboration —oxidation of terminal disubstituted olefins, can be readily synthesized using the homologation approach15. 

Further, it should be clear that if a chiral alkene such as the terpene a-pinene (Scheme 6.27) is used, and if steric effects are important, then the specificity of addition would result in a chiral borane reagent. Use of the chiral borane reagent, in, for example, oxidative hydroboration, would then produce a chiral alcohol. 

These chiral alkylboronic esters are exceptionally promising intermediates for C-C bond formation reaction in the synthesis [8, 9] of a-chiral aldehydes, P Chiral alcohols, a-chiral acids, and a-chiral amines. Brown et al [10], in a real breakthrough, discovered that LiAlH readily converts these relatively inert boronic esters to a very high reactive lithium monoalkylborohydrides R BHjLi (5) of very high optical purity. The optically active monoalkylborane (R BH2) is generated, when required, by a convenient reaction with trimethylsilyl chloride [6]. Consequently, the desired B-R -9-BBN is prepared conveniently by hydroboration of 1,5-cyclooctadiene with RBHj (prepared in situ), and the desired stable 1,5-isomer is obtained by thermal isomerization. The whole sequence is illustrated in Scheme 9.1. 

Hydrogenation of olefins, enols, or enamines with chiral tVilkinson type catalysts, e.g., Noyort hydrogenation. Hydroboration of olefins with chiral boranes. Sharpless epoxi-dation of allylic alcohols. 

The uncatalyzed hydroboration-oxidation of an alkene usually affords the //-Markovnikov product while the catalyzed version can be induced to produce either Markovnikov or /z/z-Markovnikov products. The regioselectivity obtained with a catalyst has been shown to depend on the ligands attached to the metal and also on the steric and electronic properties of the reacting alkene.69 In the case of monosubstituted alkenes (except for vinylarenes), the anti-Markovnikov alcohol is obtained as the major product in either the presence or absence of a metal catalyst. However, the difference is that the metal-catalyzed reaction with catecholborane proceeds to completion within minutes at room temperature, while extended heating at 90 °C is required for the uncatalyzed transformation.60 It should be noted that there is a reversal of regioselectivity from Markovnikov B-H addition in unfunctionalized terminal olefins to the anti-Markovnikov manner in monosubstituted perfluoroalkenes, both in the achiral and chiral versions.70,71... 

While Josiphos 41 also possessed an element of atom-centered chirality in the side chain, Reetz reported a new class of ferrocene-derived diphosphines which had planar chirality only ligands 42 and 43, which have C2- and C -symmetry, respectively.87 Rhodium(i)-complexes of ligands (—)-42 and (—)-43 were used in situ as catalysts (0.75 mol%) for the hydroboration of styrene with catecholborane 1 for 12 h in toluene at — 50 °C. The rhodium/ i-symmetric (—)-43 catalyst system was the more enantioselective of the two - ( -l-phenylethanol was afforded with 52% and 77% ee with diphosphines (—)-42 and (—)-43, respectively. In both cases, the regioselectivity was excellent (>99 1). With the same reaction time but using DME as solvent at lower temperature (—60 °C), the rhodium complex of 43 afforded the alcohol product with an optimum 84% ee. 

An asymmetric version of the Pd-catalyzed hydroboration of the enynes was reported in 1993(118]. The monodentate phosphine (S)-MeO-MOP was used as a chiral ligand for the palladium catalyst. Enantioselectivity of the asymmetric hydroboration was estimated from the enantiopurity of homopropargyl alcohols, which were obtained from the axially chiral allenylboranes and benzaldehyde via an SE pathway (Scheme 3.78). 

In 1993, Hayashi and co-workers reported a catalytic asymmetric synthesis of alle-nylboranes 256 by palladium-catalyzed hydroboration of conjugated enynes 253 (Scheme 4.66) [105]. Reaction of but-l-en-3-ynes 253 with catecholborane 254 in the presence of a catalyst, prepared from Pd2(dba)3 CHC13 (1 mol%) and a chiral mono-dentate phosphine ligand (S)-MeO-MOP 255 (1 mol%), gave an allenylborane 256. The ee of 256 was determined by the reaction with benzaldehyde affording the corresponding optically active homopropargyl alcohols 257 with up to 61% ee (syn anti= 1 1—3 1). 

A hydroboration-oxidation sequence has been described for the desymmetrization of bicyclic hydrazino-alkenes. The use of BDPP as a chiral ligand on Rh provides the desired alcohol in 84% ee, following oxidation of the hydroborated... 

Both these optically active betweenanenes exhibited a (—)-Cotton effect47 at 195 nm, indicating their (R)-configuration. Hydroboration-oxidation of these specimens gave the ( )-fused alcohols 106 whose respective optical purities (7.6 and 6.0%) were estimated by means of the NMR chiral shift reagent method. 

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