Lithium aluminum hydride alcohol modifiers

Two asymmetric synthesis approaches to chiral cyclopentenone derivatives can be envisaged. The first, reduced to practice by Noyori (43), involved reduction of cyclopentene-l,4-dione with lithium aluminum hydride chirally modified with binaphthol to give R-4-hydroxycyclopent-2-en-l-one in 94% e.e. Alternatively, manganese dioxide oxidation of allylic alcohol [40] (Fig. 7), in analogy to the cis isomer (54), would be expected to give the same enone. 

N-Methylation of 3 and reduction of the crystalline oxazolidinone 4 with lithium aluminum hydride was found to give a superior yield of DAIB (5) and a more easily purified product than exhaustive methylation of 2 with methyl iodide and reduction of the quaternary methiodide with Super-Hydride. Recently, a modified version of DAIB, 3-exo-morpholinoisoborneol MIB), was prepared by Nugent that is crystalline and that is reported to give alcohols in high enantiomeric excess from the reaction of diethylzinc with aldehydes. ... 

The most general way to obtain chiral a-stannylated ethers today consists of the asymmetric reduction of acylstannanes34,35,36 using the 2,2 -dihydroxy-l,T-binaphthyl-modified lithium aluminum hydride (BINAL-H) reagent37 and etherification of the crude alcohol with chloro-methoxymethane. 

The enantioselective reduction of unsymmetrical ketones to produce optically active secondary alcohols has been one of the most vibrant topics in organic synthesis.8 Perhaps Tatchell et al. were first (in 1964) to employ lithium aluminum hydride to achieve the asymmetric reduction of ketones9 (Scheme 4.IV). When pinacolone and acetophenone were treated with the chiral lithium alkoxyaluminum hydride reagent 3, generated from 1.2 equivalents of 1,2-0-cyclohexylidene-D-glucofuranose and 1 equivalent of LiAlHzt, the alcohol 4 was obtained in 5 and 14% ee, respectively. Tatchell improved the enantios-electivity in the reduction of acetophenone to 70% ee with an ethanol-modified lithium aluminum hydride-sugar complex.10... 

In 1979, Noyori and co-workers invented a new type of chiral aluminum hydride reagent (1), which is prepared in situ from LiAlEE, (S)-l, E-bi-2-naphthol (BINOL), and ethanol. The reagent, called binaphthol-modified lithium aluminum hydride (BINAL-H), affects asymmetric reduction of a variety of phenyl alkyl ketones to produce the alcohols 2 with very high to perfect levels of enantioselectivity when the alkyl groups are methyl or primary1 (Scheme 4.3a). 

The binaphthol-modified lithium aluminum hydride reagents (BINAL-Hs) are also effective in enantioselective reduction of a variety of alkynyl and alkenyl ketones2 (Scheme 4.3b). When the reaction is carried out with 3 equivalents of (S)-BINAL-H at —100 to —78 C, the corresponding propargylic alcohol 3 and allylic alcohol 4 are obtained in high chemical yields with good to excellent levels of enantioselectivity. As is the case with aryl alkyl ketones, the alcohols with (.V)-con figuration are obtained when (S)-BINAL-H is employed. 

Chiral Ligand of L1A1H4 for the Enantioselective Reduction of Alkyl Phenyl Ketones. Optically active alcohols are important synthetic intermediates. There are two major chemical methods for synthesizing optically active alcohols from carbonyl compounds. One is asymmetric (enantioselective) reduction of ketones. The other is asymmetric (enantioselective) alkylation of aldehydes. Extensive attempts have been reported to modify Lithium Aluminum Hydride with chiral ligands in order to achieve enantioselective reduction of ketones. However, most of the chiral ligands used for the modification of LiAlHq are unidentate or bidentate, such as alcohol, phenol, amino alcohol, or amine derivatives. 

In 1951 Bothner-By first attempted asymmetric reductions based on the conversion of lithium aluminum hydride (LAH) into a chiral alkoxy derivative by reaction with (+)-camphor. Since this pioneering work, the use of chirally modified LAH reagents has been the focus of much attention. In 1979, the first virtually complete enantiofacial recognition of prochiral carbonyl compounds was accomplished by using LAH modified with optically pure 2,2 -dihydroxy-1,1 -binaphthyl and a simple alcohol (BINAL-H). Asymmetric reduction with chiral 2,5-dimethylborolane also gave alcohols in high optical yields." Recently, excellent results have been obtained using a chirally modified sodium borohydride... 

Hofmann degradation, styrene 468 was formed. Epoxidation of 468 with m-chloroperbenzoic acid from the less hindered side and lithium aluminum hydride reduction gave ( )-epicorynoline (469). Moreover, slow addition of the a-methoxystyrene 471 to isoquinolinium salt 470 gave cycloadduct 472 in 90% yield. The adduct was hydrolyzed by acid and the resultant aldehyde oxidized to naphthoic acid by Jones oxidation. Modified Curtius rearrangement of 473 with added benzyl alcohol afforded benzyl urethane 474, which was reduced by lithium aluminum hydride and formylated with chloral to give 0-methylarnottiamide (475) (Scheme 60). 

Diphenylcyclopropane has been prepared previously by (1) the Simmons-Smith procedure (24% yleld) b,19 and modified versions of this method (up to 72%),20 (2) sulfonium ylide addition to 1,1-diphenylethene (61% yield),21 (3) reduction of 1,1-diphenyl-2,2-dihalocyclopropanes with sodium in ammonia (47% yield),22 with sodium and tert-butyl alcohol (80%), or with diethyl lithiomethanephosphonate (62%),23 (4) base-promoted cyclization of trimethyl(3,3-diphenylpropyl)ammonium iodide (78%),24 (5) boron trifluorlde-promoted cyclization of a corresponding 3-hydroxypropyistannane (97%),2 (6) reaction of 3,3-diphenylpropenoic acid with lithium aluminum hydride (62%),2 (7) reaction of... 

The asymmetric reduction of ketones with modified lithium aluminum hydride is well known. Several reviews of the literature are available2-4-7, as is a comparison of the relative effectiveness of a variety of reagents8. Many of the early studies used terpenoid or carbohydrate-derived alcohols as modifiers, however, ketone reduction rarely proceeded with greater than 20% ee. One problem with these reagents is that the alkoxy aluminum reagent may undergo exchange so that lithium aluminum hydride could be present in solution. 

A second and more general problem is that there are very few structural characterizations or mechanistic studies on any of these modified lithium aluminum hydride reagents. Thus, it is difficult to predict the absolute configuration of the product alcohol and to rationally design better reagents. 

Table 3. Optically Active Secondary Alcohols by Reduction of Ketones with Modified Lithium Aluminum Hydride Reagents...

A variety of amino alcohols have been examined as modifiers for lithium aluminum hydride. The most effective are 2-dimethylamino-l-phenyl-l-propanol (A-methylephedrine) and ( + )-(2S,3/ )-4-dimethylamino-3-methyl-l,2-diphenyl-2-butanol (Darvon alcohol or Chirald). 

A more complex diamino alcohol, ( S,)-3-methylamino-4-phenylamino-l-butanol [from (S)-aspartic acid], is also an effective modifier for lithium aluminum hydride reductions65. 

Both enantiomers of binaphthol have found many uses as chiral reagents and catalysts. Thus, they modify reducing agents (e.g., lithium aluminum hydride) for the reduction of ketones to chiral secondary alcohols (Section D.2.3.3.2.) or react with aluminum, titanium or boron compounds to give chiral Lewis acids for asymmetric Diels-Alder reactions (Section D. 1.6.1.1.1.3.) and ene reactions (Section D.I.6.2.). They have also been used as chiral leaving groups in the rearrangement of allyl ethers (Section D.l.1.2.2.) and for the formation of chiral esters with a-oxo acids (Section D. 1.3.1.4.1, and many other purposes. 

Functional groups may already be present in the polymer structures of the chemicals or can be added to the surface by various chemical treatments, depending on the molecular configuration of the specific polymer required for modification. For example, the polymer PMMA, which consists of methyl ester groups, can be chemically modified by a simple reduction reaction to alcohols, with lithium aluminum hydride in ether-based solutions, followed by the widely used organosilane... 

We can convert an acyl chloride into an aldehyde by hydride reduction. In this transformation, we again face a selectivity problem Sodium borohydride and lithium aluminum hydride convert aldehydes into alcohols. To prevent such overreduction, we must modify LiAlH4 by letting it react first with three molecules of 2-methyl-2-propanol (fert-butyl alcohol see Section 8-6). This treatment neutralizes three of the reactive hydride atoms, leaving one behind that is nucleophilic enough to attack an acyl chloride but not the resulting aldehyde. 

One of the more difficult partial reductions to accomplish is the conversion of a carboxylic acid derivative to an aldehyde without over-reduction to the alcohol. Aldehydes are inherently more reactive than acids or esters so the challenge is to stop the reduction at the aldehyde stage. Several approaches have been used to achieve this objective. One is to replace some of the hydrogens in a group III hydride with more bulky groups, thus modifying reactivity by steric factors. Lithium tr i - / - b u to x y a I u m i n u m hydride is an example of this approach.42 Sodium tri-t-butoxyaluminum hydride can also be used to reduce acyl chlorides to aldehydes without over-reduction to the alcohol.43 The excellent solubility of sodium bis(2-methoxyethoxy)aluminum hydride makes it a useful reagent for selective... 

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