Ketones, cyclic reduction with hydride

A similar chiral environment is given by inclusion to cyclodextrins (CDs), cyclic oligosaccharides (3). The outside of the host molecule is hydrophilic and the inside hydrophobic. The diameters of the cavities are approximately 6 (a), 7-8 (j3), and 9-10 A (7), respectively. Reduction of some prochiral ketone-j3-CD complexes with sodium boro-hydride in water gives the alcoholic products in modest ee (Scheme 2) (4). On the other hand, uncomplexed ketones are reduced with a crystalline CD complex of borane-pyridine complex dispersed in water to form the secondary alcohols in up to 90% ee, but in moderate chemical yields. Fair to excellent enantioselection has been achieved in gaseous hydrohalogenation or halogenation of a- or /3-CD complexes of crotonic or methacrylic acid. These reactions may seem attractive but currently require the use of stoichiometric amounts of the host CD molecules. 

Stereoselectivity in the reaction of acyclic ketone 270 is different from that of the cyclic ketone 256. The acetate in 271, prepared by reduction of the ketone 270 to alcohol with LiAlH and acetylation, was displaced with Me A1 from the exo side to give 272 with retention of the stereochemistry. No racemization of benzyl cation was observed. However, reaction of 270 with MeLi gave 274. The OH group of 274 was removed with hydride from the less hindered side as shown by 275 to give 276 with... 

Other cyclic or bicyclic ketones do not have a convex side but only a less concave and a more concave side. Thus, a hydride donor can add to such a carbonyl group only from a concave side. Because of the steric hindrance, this normally results in a decrease in the reactivity. However, the addition of this hydride donor is still less disfavored when it takes place from the less concave (i.e., the less hindered) side. As shown in Figure 10.10 (top) by means of the comparison of two reductions of norbomanone, this effect is more noticeable for a bulky hydride donor such as L-Selectride than for a small hydride donor such as NaBH4. As can be seen from Figure 10.10 (bottom), the additions of all hydride donors to the norbomanone derivative B (camphor) take place with the opposite diastereoselectivity. As indicated for each substrate, the common selectivity-determining factor remains the principle that the reaction with hydride takes place preferentially from the less hindered side of the molecule. 

The starting material for the present synthesis was Wieland-Miescher ketone (24), which was converted to the known alcohol (25) by the published procedure [10], Tetrahydropyranylation of alcohol (25) followed by hydroboration-oxidation afforded the alcohol (26), which on oxidation produced ketone (27). Reduction of (27) with metal hydride gave the alcohol (28) (56%). This in cyclohexane solution on irradiation with lead tetraacetate and iodine produced the cyclic ether that was oxidized to obtain the keto-ether (29). Subjection of the keto-ether (29) to three sequential reactions (formylation, Michael addition with methyl vinyl ketone and intramolecular aldol condensation) provided tricyclic ether (30) whose NMR spectrum showed it to be a mixture of C-10 epimers. The completion of the synthesis of pisiferic acid (1) did not require the separation of epimers and thus the tricyclic ether (30) was used for the next step. The conversion of (30) to tricyclic phenol (31) was... 

CBS reductions are best when the ketone s two substituents are well-differentiated sterically— just as Ph and Me are in the example above. Only when the ketone is complexed with the other boron atom (in the ring) is it electrophilic enough to be reduced by the weak hydride source. The hydride is delivered via a six-membered cyclic transition slate, with the enantioselectivity arising from the preference of the larger of the ketone s two substituents (RL) for the pseudoequatorial position on this ring. 

Reduction of cyclic ketones. Competitive reductions of cyclic ketones of various types with lithium tri-/-butoxyaluminum hydride indicate that nonconjugated cnones are less reactive than cyclic staturaled ketones, but more reactive than conjugated cnones. Steric effects do not appear to be important, since 3-ketocyclohe ene (1) is less... 

This new reagent is an active reducing agent and reduces cyclic and bicyclic ketones with supcrstcreoselectivity. Thus reduction of 2-mcthylcyclohexanone (I) gives rw-2-methylcyclohexanol in 99.3 (, purity. Note that reduction with lithium trimethoxy-aluminum hydride alone yields (2) in 69% yield. Thus increasing the size of the alkyl substituents on boron enhances the stereoselectivity of the borohydride anion. Even... 

Reductions of cyclic ketones by dissolving metals are frequently highly stereoselective and these reductions have been used to obtain secondary alcohols which are difficult or impossible to prepare by metal hydride reduction. In terms of yield, the best results are usually obtained either by reductions with alkali metals (commonly Li) in liquid NH3 in the presence of proton donors or with active metals in an alcohol. Although a number of explanations have been advanced for the stereoselectivity of these reductions, they are all rationalizations with dubious predictive value." There are, however, a number of empirical generalizations which are based on a considerable body of experimental data, specifically ... 

The only asymmetric synthesis of the Nuphar indolizidine to date is due to Barluenga and co-workers (615). Their route to the (5S,8 ,8aS)-( -) enantiomer of 944 commenced with cycloaddition between the proline-derived 2-amino-butadiene 957 and imine 958 (Scheme 125). Hydrolysis of the adduct 959 gave piperidinone 960 in 51% yield and an ee of better than 99%. Once the alcohol and amine groups had been mutually protected as the cyclic carbamate 961, defimctionalization of the ketone was accomplished via an enol triflate. Chain-extension of the deprotected piperidine 962 at the hydroxymethyl substituent afforded 963, which was cyclized to the bicyclic lactam 964 simply by heating in toluene. Reduction with lithium aluminum hydride completed the synthesis of ( - )-944 ([a]n -99°, c 1.3, CH2CI2). 

The lithium 9-boratabicyclo[3.3.1]nonane (Li 9-BBNH) is prepared [1] by refluxing 1 equiv of 9-BBN with excess of finely divided lithium hydride. The reagent reduces [2] cyclic ketones, and the hydride adds from the less hindered side. For example, camphor on reduction with Li 9-BBNH affords the less stable exo isomer isoborneol in 91% yield (Eq. 26.36). 

Reductive amination of carbonyl compounds is a synthetically attractive process because it directly transforms aldehyde and ketones into the primary and secondary amines 229 (Scheme 105). Among a number of screened catalysts, the best proved to be the rhodium complex 74. The reaction proceeded with a high selectivity in the presence of HCOONH4 as hydride and amine source with linear and cyclic ketones, and also with ketoacids [143]. 

There are also reactions in which hydride is transferred from carbon. The carbon-hydrogen bond has little intrinsic tendency to act as a hydride donor, so especially favorable circumstances are required to promote this reactivity. Frequently these reactions proceed through a cyclic TS in which a new C—H bond is formed simultaneously with the C-H cleavage. Hydride transfer is facilitated by high electron density at the carbon atom. Aluminum alkoxides catalyze transfer of hydride from an alcohol to a ketone. This is generally an equilibrium process and the reaction can be driven to completion if the ketone is removed from the system, by, e.g., distillation, in a process known as the Meerwein-Pondorff-Verley reduction,189 The reverse reaction in which the ketone is used in excess is called the Oppenauer oxidation. 

New chiral oxazaborolidines that have been prepared from both enantiomers of optically active inexpensive a-pinene have also given quite good results in the asymmetric borane reduction of prochiral ketones.92 Borane and aromatic ketone coordinate to this structurally rigid oxazaborolidine (+)- or (—)-94, forming a six-membered cyclic chair-like transition state (Scheme 6-41). Following the mechanism shown in Scheme 6-37, intramolecular hydride transfer occurs to yield the product with high enantioselectivity. With aliphatic ketones, poor ee is normally obtained (see Table 6-9). 

Ashby and Yu have studied the kinetics of reduction of benzophenone with TIBA in ether and showed that the overall kinetic rate expression is second order, first order in TIBA and first order in ketone (151). The observed activation parameters were AG - 18.8 kcal/mol AH = 15.8 kcal/mol and AS = - 10.1 e.u. The negative entropy of activation is consistent with a cyclic transition state for the rate-determining hydride-transfer step. A Hammett study gave a value of p = 0.362, supporting nucleophilic attack by the aluminum alkyl on the carbonyl group in the rate-determining step. 

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